Comparison of the efficacy and safety of different dose anlotinib in combination with immune checkpoint inhibitors for patients with advanced non-small cell lung cancer

Comparison of the efficacy and safety of different dose anlotinib in combination with immune checkpoint inhibitors for patients with advanced non-small cell lung cancer | 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 Comparison of the efficacy and safety of different dose anlotinib in combination with immune checkpoint inhibitors for patients with advanced non-small cell lung cancer Tingfei Tan, Siyu Yuan, Weiwei Chu, Jiemei Jiang, Meiling Chen, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4453491/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 Purpose: The combination of anlotinib with immune checkpoint inhibitors (ICIs) has become a common treatment modality in clinical practice. However, the optimal dose of anlotinib to use remains unclear. Methods: We collected patients with advanced non-small cell lung cancer (NSCLC) who received programmed cell death-1 (PD-1) or programmed cell death ligand 1 (PD-L1) blockade combined with different dose anlotinib as second-line or later line therapy. Subsequently, the efficacy and safety of the combination therapy as well as subgroup analyses of different doses of anlotinib were analyzed. Cox regression was performed to analyze significant factors correlated with progression-free survival (PFS) and overall survival (OS). Results: A total of 50 eligible patients with NSCLC who received anlotinib combined with ICIs therapy were included, of which 27 received low-dose anlotinib (8 mg), and 23 were administered high-dose anlotinib (12 mg). The median PFS (mPFS) and the median OS (mOS) for all patients were 8.3 months (95% CI 6.3–10.3) and 17.6 months (95% CI 16.5–18.7), respectively. Subgroup analyses showed that patients treated with 8 mg of anlotinib plus ICIs had significantly longer mPFS than those treated with 12 mg of amlotinib plus ICIs (8.7 months vs 6.7 months; p=0.016). The overall incidence of adverse events (AEs) was 68.0%, and the most common AEs of all grades were hypertension. Meanwhile, the incidence of adverse events was higher for 12 mg of anlotinib plus ICIs than that of 8 mg of anlotinib plus ICIs(82.6% vs 55.6%, P = 0.041). Conclusion: Low-dose anlotinib in combination with ICIs for advanced NSCLC may be an effective and well-tolerated option. advanced non-small cell lung cancer low-dose anlotinib immune checkpoint inhibitors PD-1/PD-L1 combination therapy Figures Figure 1 Figure 2 Introduction The Global Cancer Report 2020 showed that there were approximately 2.2 million new cases of lung cancer and 1.8 million deaths, accounting for approximately 11.4% of newly diagnosed cancers and 18.0% of deaths (Sung et al. 2021 ). Lung cancer is the leading cause of cancer-related deaths globally, and non-small cell lung cancer (NSCLC) accounts for about 83% of lung cancer cases, most of which are locally advanced or metastatic at the time of diagnosis as well as have a poor prognosis (Miller et al. 2019 ). The advent of immune checkpoint inhibitors (ICIs) has provided new strategies for the treatment of advanced NSCLC. A growing body of evidence suggests that immune checkpoint inhibitors, such as antibodies against programmed cell death-1 (PD-1) or its ligand programmed cell death-ligand 1 (PD-L1), significantly improve outcomes and prolong Overall survival (OS) in patients with advanced NSCLC (Brahmer et al. 2015 ; Borghaei et al. 2015 ; Garassino et al. 2020 ). However, not all patients benefit from ICIs alone. Some patients even over-progress after treatment with single ICIs (Kim et al. 2019 ). Therefore, it is important to explore combination therapy regimens with ICIs for the benefit of patients with advanced NSCLC. Angiogenesis plays a very important role in cancer progression (Claesson-Welsh and Welsh 2013 ; Casanovas et al. 2005 ). Tumor growth and metastasis depend on abundant blood vessels, so blocking the pathways of tumor angiogenesis is an effective therapeutic strategy. Anlotinib is a tyrosine kinase inhibitor (TKI) that targets a wide range of tumor vascular and proliferative signaling receptors (Shen et al. 2018 ; Lin et al. 2018 ). Currently, anlotinib has been approved by China National Medical Products Administration for use in two types of advanced NSCLC patients who have progressed after chemotherapy (Syed 2018 ). Some studies have shown that the combination of anlotinib and ICIs has a synergistic effect. For patients with advanced NSCLC without epidermal growth factor receptor (EGFR) mutations, the combination of anlotinib and ICIs has good efficacy and tolerance as first-line therapy (Chu et al. 2021 ). In second-line and beyond, anlotinib plus ICIs produced higher objective effectiveness rates (ORR) and longer progression-free survival (PFS) compared to ICIs monotherapy (Zhang et al. 2021 ). These studies confirm that the combination of anlotinib with ICIs can improve the treatment outcome of NSCLC patients. Based on the concept of a positive correlation between efficacy and dose, the 12 mg dose of anlotinib was frequently combined with ICIs in most studies (Sun et al. 2016 ). Interestingly, a series of studies have presented that using a lower dose results in a more homogeneous distribution of tumor vasculature compared to higher doses of antiangiogenic drugs (Huang et al. 2012 ; Van der Veldt et al. 2012 ; Huang et al. 2013 ; Zhao et al. 2019 ). Specifically, apatinib (a TKI drug similar to anlotinib) is better at normalizing tumor blood vessels when used at low doses. When combined with ICIs, the synergistic effect of low-dose apatinib was significantly higher than that of high dose (Zhao et al. 2019 ). In addition, low-dose apatinib better reprogrammed the tumor microenvironment from an immunosuppressive to an immunologically permissive microenvironment (Fukumura et al. 2018 ). Therefore, the application of low-dose combination of antiangiogenic drugs and ICIs may have better antitumor synergistic effects than the high-dose combination group. Anlotinib in combination with ICIs as a therapeutic strategy is becoming more widely in patients with NSCLC. However, the optimal combined dose of anlotinib remains to be determined. Here, we conducted this retrospective study to look at the status of anlotinib plus ICIs in the real world. Subgroups of results were also performed to compare the efficacy and safety of ICIs in combination with high dose (12mg) or low dose (8mg) of anlotinib. This study provides a reference for the clinical application of anlotinib combined with ICIs. Patients and Methods Study Design and Patients Patients diagnosed with advanced NSCLC who received 8 mg or 12 mg anlotinib in combination with ICIs as second-line or later therapy between February 2021 and August 2022 at the First Affiliated Hospital of Anhui Medical University in China were included. Further, the inclusion criteria were as follows: age ≥ 18 years; advanced stage (IIIB-IV) NSCLC were pathological identified; at least one measurable lesion; Eastern Cooperative Oncology Group (ECOG) ≤ 3. While exclusion criteria were: mixed tumors of small cell and NSCLC ; active bleeding or serious systemic diseases; any adjust the dosage of anlotinib during treatment; any have not received follow-up information within two cycles after taking anlotinib. The clinical information system (donghua software) was performed to collect baseline characteristics, including gender, age, dose, ECOG score, pathological type, clinical stage, smoking history, gene mutation, treat line, hypertension, prior targeted therapy, prior anti-angiogenesis treatment, prior thoracic radiotherapy. Treatment Anlotinib was administered once daily (12 mg or 8 mg) on days 1–14 of a 21-day cycle. The initial dose of anlotinib was determined by the oncologist according to the patients’ status. ICIs was treated with PD-1 or PD-L1 antibodies including Camrelizumab (200 mg every 3 weeks) pembrolizumab ( 200mg every 3 weeks ), nivolumab (3 mg/kg every 2 weeks), sintilimab (200 mg every 3 weeks), toripalimab (240 mg every 3 weeks), or durvalumab (10mg/kg every 2 weeks). Follow-up data were collected up to October 30th, 2023. This study was approved by the First Affiliated Hospital of Anhui Medical University (No. Quick-PJ2019-14-15) and conducted according to the principles of the Declaration of Helsinki. Given the retrospective analysis, the requirement for individual consent was waived. Efficacy and Safety Assessments Therapeutic responses were assessed based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 every 2 cycles, defined as complete response (CR), partial response (PR), stable disease (SD) and progression disease (PD). PFS was characterized as the time between the date of the start of treatment with both anlotinib and ICIs, and the documented disease progression or death from any cause. Overall survival (OS) was defined as the time from initiation of treatment to death or last follow-up. ORR referred to the proportion of patients who have complete or a partial response to the therapy. Disease control rate (DCR) was defined as the proportion of patients with partial response (PR), complete response (CR), and stable disease (SD). Adverse reactions (AEs) were graded using the Common Terminology Criteria for Adverse Events version 5.0(CTCAE 5.0). Statistical Analysis The baseline clinical features of all patients were summarized as categorical (percentage) and continuous data (mean and standard). Pearson Chi-square test was used to compare categorical variables and tumor responses between two groups. Comparison between groups for continuous variables were performed by an independent-sample t-test. The median PFS, OS, and 95% confidence interval (CI) were estimated using the Kaplan–Meier method. Cox proportional hazards regression was carried out by the univariable and multivariable analyses and to calculate the hazard ratios (HR) with 95% CIs. All statistical analyses were performed using Statistical Products and Services Solutions, version 26 (SPSS 26.0). Results Baseline Clinical Characteristics of Patients A total of 50 patients were included in the analysis, of whom 31 (62.0%) were male and 19 (38.0%) were female. Among the patients, the mean age was 60.93 ± 10.15. And there were 27 patients (54.0%) taking 8 mg of anlotinib, and 23 patients (46.0%) taking 12 mg of anlotinib. Besides, a total of 9 patients (18.0%) had a smoking history and 45 patients (90.0%) had an ECOG of 0–1. The pathological diagnosis of the patient included squamous carcinoma (44.0%, 22/50) and adenocarcinoma (56.0%, 28/50). Of those, 25 (25.0%) patients received 3rd line or later line treatment with anlotinib. Overall, Stage IV disease was present in 42 patients (84.0%), gene mutations were identified in 15 patients (30.0%). Regarding treatment, 11 (22.0%) patients received prior targeted therapy. 18 patients (36.0%) were treated with prior anti-angiogenesis therapy. Additionally, 15 patients (30.0%) had previously undergone thoracic radiotherapy. The detailed baseline clinical characteristics of patients are listed in Table 1 . Table 1 Baseline Clinical Characteristics of Patients Basic Characteristics No. of patients (%) Gender Male 31(62.0) Female 19(38.0) Age Mean ± standard 60.93 ± 10.15 Doses of anlotinib 8mg 27(54.0) 12mg 23(46.0) ECOG score 0–1 45(90.0) ≥ 2 5(10.0) Pathological type Squamous carcinoma 22(44.0) Adenocarcinoma 28(56.0) Clinical stage <IV 8(16.0) IV 42(84.0) Smoking history Yes 9(18.0) No 41(82.0) Gene mutation Yes 15(30.0) No 35(70.0) Treat line 2 25(50.0) ≥ 3 25(50.0) Prior targeted therapy Yes 11(22.0) No 39(78.0) Prior anti-angiogenesis treatment Yes 18(36.0) No 32(64.0) Prior thoracic radiotherapy Yes 15(30.0) No 35(70.0) ECOG Eastern Cooperative Oncology Group Overall Efficacy of Treatment In the entire cohort, the median PFS (mPFS) of patients was 8.3 months (95% CI 6.3–10.3), and the median OS (mOS) was 17.6 months (95% CI 16.5–18.7) (Fig. 1 A and Fig. 1 B). Moreover, univariate analysis were performed to identify potential factors that associated with PFS and OS in all patients (Table 2 ), meanwhile the statistically significant factors (P < 0.05) were included into multivariate Cox regression analysis. Data revealed that gender (male vs female: HR = 3.288, 95% CI 1.712–6.313, P = 0.000), and ICIs combined with different dose anlotinib (8mg vs 12mg: HR = 2.110, 95% CI 1.154–3.858, P = 0.015) were identified as the independent influencing factors of PFS. Similarly, the independent factors influencing OS were gender (male vs female: HR = 2.449, 95%CI 1.305–4.597, P = 0.005), and ICIs combined with anlotinib (8mg vs 12mg: HR = 1.843, 95% CI 1.029-3.300, P = 0.040) as well (Table 3 ). Table 2 Univariate Cox Regression Analyses of PFS and OS Variable PFS OS HR 95% CI p-value HR 96% CI p-value Gender (male vs female) 3.169 1.667–6.022 0.000 2.298 1.231–4.289 0.009 Age (< 65 years vs ≥ 65 years) 0.684 0.384–1.219 0.198 0.823 0.454–1.491 0.521 ICIs combined with anlotinib (8mg vs 12mg) 2.033 1.120–3.690 0.020 1.708 0.958–3.044 0.069 ECOG score (0–1 vs ≥ 2) 1.866 0.728–4.785 0.194 1.108 0.435–2.823 0.830 Pathological type (Squamous carcinoma vs Adenocarcinoma) 0.701 0.387–1.270 0.241 0.703 0.386–1.282 0.250 Clinical stage(<IV vs IV) 0.565 0.260–1.231 0.151 0.556 0.255–1.215 0.141 Smoking history (yes vs no) 0.944 0.468–1.904 0.873 0.950 0.471–1.915 0.885 Gene mutation (yes vs no) 1.533 0.820–2.867 0.181 1.200 0.640–2.252 0.569 Treat line (2 vs ≥ 3) 1.155 0.657–2.031 0.617 1.114 0.634–1.957 0.708 Previous targeted therapy (yes vs no) 1.972 0.979–3.973 0.058 1.404 0.703–2.804 0.336 Previous anti-angiogenesis therapy (yes vs no) 0.939 0.512–1.722 0.839 0.944 0.524–1.699 0.847 Previous thoracic radiotherapy (yes vs no) 0.630 0.320–1.239 0.181 0.626 0.321–1.223 0.171 ICIs Immune checkpoint inhibitors, ECOG Eastern Cooperative Oncology Group, HR hazard ratio, CI confidence interval, PFS progression-free survival, OS overall survival. Table 3 Multivariate Cox Regression Analysis of PFS and OS Variable PFS OS HR 95% CI p-value HR 96% CI p-value Gender (male vs female) 3.288 1.712–6.313 0.000 2.449 1.305–4.597 0.005 ICIs combined with anlotinib (8mg vs 12mg) 2.110 1.154–3.858 0.015 1.843 1.029-3.300 0.040 ICIs Immune checkpoint inhibitors, HR hazard ratio, CI confidence interval, PFS progression-free survival, OS overall survival Efficacy of low-dose anlotinib plus ICIs VS high-dose anlotinib plus ICIs Baseline characteristics were comparable between 8 mg of anlotinib plus ICIs and 12 mg of anlotinib plus ICIs (Table 4 ). Further data showed that patients receiving 8 mg of anlotinib + ICIs (n = 27, 8.7 months) had significantly longer mPFS compared to those receiving 12 mg of anlotinib + ICIs (n = 23, 6.7 months, p = 0.016; Fig. 2 A). In addition, patients treated with 8 mg of anlotinib in combination with ICIs was associated with longer mOS than patients treated with 12 mg of anlotinib in combination with ICIs, although the difference was not statistically significant (18.5 months vs. 14.3 months, P = 0.065; Fig. 2 B). However, 8 mg of anlotinib plus ICIs and 12 mg of anlotinib plus ICIs were similar in terms of ORR (18.5% vs 13.0%, P = 0.889) and DCR (85.2% vs 82.6%, P = 1.000, Table 5 ). Overall, patients treated with low-dose anlotinib in combination with ICIs had longer survival than those treated with high-dose anlotinib. Table 4 Comparison of Baseline Characteristics Between 8 mg of anlotinib plus ICIs and 12 mg of anlotinib plus ICIs Basic Characteristics 8 mg of anlotinib plus ICIs (n = 27) 12 mg of anlotinib plus ICIs (n = 23) t/X 2 p-value Gender Male 17(63.0) 14(60.9) 0.023 0.879 Female 10(37.0) 9(39.1) Age Mean ± standard 63.43 ± 7.95 60.93 ± 11.73 0.869 0.389 deviation < 65 14(51.9) 14(60.9) 0.410 0.522 ≥ 65 13(48.1) 9(39.1) ECOG score 0–1 23(85.2) 22(95.7) 0.573 0.449 ≥ 2 4(14.8) 1(4.3) Pathological type Squamous carcinoma 12(44.4) 10(56.5) 0.005 0.945 Adenocarcinoma 15(55.6) 13(43.5) Clinical stage <IV 4(14.8) 4(17.4) 0.000 1.000 IV 23(85.2) 19(82.6) Smoking history Yes 5(18.5) 4(17.4) 0.000 1.000 No 22(81.5) 19(82.6) Gene mutation Yes 8(29.6) 7(30.4) 0.004 0.951 No 19(70.4) 16(69.6) Treat line 2 15(55.6) 10(43.5) 0.725 0.395 ≥ 3 12(44.4) 13(56.5) Prior targeted therapy Yes 6(22.2) 5(21.7) 0.002 0.967 No 21(77.8) 18(78.3) Prior anti-angiogenesis treatment Yes 13(48.1) 5(21.7) 3.76 0.053 No 14(51.9) 18(78.3) Prior thoracic radiotherapy, n (%) Yes 5(18.5) 10(43.5) 3.685 0.055 No 22(81.5) 13(56.5) ICIs Immune checkpoint inhibitors, ECOG Eastern Cooperative Oncology Group Table 5 Response of 8 mg of anlotinib plus ICIs and 12 mg of anlotinib plus ICIs Response 8 mg of anlotinib plus ICIs (n = 27) 12 mg of anlotinib plus ICIs (n = 23) X 2 P-value CR 0 1 PR 5 2 SD 18 16 PD 4 4 ORR, (%) 5(18.5%) 3(13.0%) 0.019 0.889 DCR, (%) 23(85.2%) 19(82.6%) 0.000 1.000 ICIs Immune checkpoint inhibitors, CR complete response, PR partial response, SD stable disease, PD progression disease, ORR Objective Response Rate, DCR Disease control rate Safety In this analysis, treatment-related adverse events occurred in 34 of the 50 patients. The five most common adverse events (all grades) were hypertension (24.0%), hand-foot syndrome (16.0%), fatigue (16.0%), thyroid dysfunction (12.0%), and hoarseness (12.0%). The five most common ≥ 3 grade adverse events were hypertension (6.0%), hand-foot syndrome (2.0%). There were no treatment-related deaths or life-threatening adverse events. Furthermore, the most common adverse reaction was hypertension, followed by hand-foot syndrome and fatigue, regardless of whether ICIs was combined with 8 mg or 12 mg of anlotinib. Notably, compared with low-dose anlotinib plus ICIs, high-dose anlotinib plus ICIs resulted in an increased incidence of adverse events of all grades, although no new adverse reactions were observed (55.6% vs 82.6%, P = 0.041). The incidence of grade 3 or above adverse reactions was similar between the two groups (13.0% vs 3.7%; P = 0.49). The adverse reactions are listed in Table 6 . Table 6 Adverse events in patients treated with 8 mg of anlotinib plus ICIs and 12 mg of anlotinib plus ICIs Adverse event All Patients (n = 50) 8 mg of anlotinib plus ICIs (n = 27) 12 mg of anlotinib plus ICIs (n = 23) Any grade (%) ≥ 3 grade (%) Any grade (%) ≥ 3 grade (%) Any grade (%) ≥ 3 grade (%) Hypertension 12(24.0) 3(6.0) 6(22.2) 1(3.7) 6(26.1) 2(8.7) Hand-foot syndrome 8(16.0) 1(2.0) 2(7.4) 0(0.0) 6(26.1) 1(4.3) Fatigue 8(16.0) 0(0.0) 3(11.1) 0(0.0) 5(21.7) 0(0.0) Gastrointestinal reaction 4(8.0) 0(0.0) 1(3.7) 0(0.0) 3(13.0) 0(0.0) Thyroid dysfunction 6(12.0) 0(0.0) 1(3.7) 0(0.0) 5(21.7) 0(0.0) Proteinuria 4(8.0) 0(0.0) 1(3.7) 0(0.0) 3(13.0) 0(0.0) Hoarseness 6(12.0) 0(0.0) 2(7.4) 0(0.0) 4(17.4) 0(0.0) Rash 2(4.0) 0(0.0) 1(3.7) 0(0.0) 1(4.3) 0(0.0) Liver dysfunction 3(6.0) 0(0.0) 1(3.7) 0(0.0) 2(8.7) 0(0.0) Hemoptysis 2(4.0) 0(0.0) 0(0.0) 0(0.0) 2(8.7) 0(0.0) Hypertriglyceridemia 1(2.0) 0(0.0) 0(0.0) 0(0.0) 1(4.3) 0(0.0) ICIs Immune checkpoint inhibitors Discussion The combination of antiangiogenic agents and ICIs has shown definite efficacy in a variety of solid tumors (Manegold et al. 2017 ). Similarly, the results of retrospective studies of anlotinib plus ICIs are promising treatment. In one hand, the mPFS for third-line treatment of NSCLC with anlotinib alone was 5.4 months and the mOS was 9.6 months (Han et al. 2018 ). Surprisingly, the combination therapy in our study had mPFS, mOS of 8.3 months, 17.6 months, and 16% ORR respectively, which provided an additional 2.9 months of PFS and 8.0 months of OS benefit compared with anlotinib alone. In the other hand, favorable efficacy was obtained with combination therapy compared to PD-1 blockade alone. In the PD-1 blockade alone trial (KEYNOTE-001), ORR, mPFS, and mOS values were 19.4%, 3.7 months, and 12.0 months, respectively (Garon et al. 2015 ). The comparison of our data shows that the combination therapy is highly effective. Consistent with our conclusion, others have also confirmed that anlotinib in combination with ICIs has a favourable therapeutic effect in NSCLC (Wang et al. 2021 ). In terms of the mechanism, the combination of anlotinib and ICIs has a synergistic effect to regulate the tumor immune microenvironment, such as promoting the infiltration of natural killer cells, M1-like tumor-associated macrophages (TAMs), and dendritic cells, while decreasing the infiltration of M2-like TAMs (Yang et al. 2020 ). In addition, anlotinib is able to inactivate the AKT pathway reducing PD-L1 expression on vascular endothelial cells, leading to an elevation in the CD8/FoxP3, thus activating the immune response (Liu et al. 2020 ). Anti-angiogenic agents work by pruning tumor blood vessels and limiting nutrient supply to tumor cells (Eelen et al. 2020 ). In vivo and in vitro studies demonstrated that relatively low-dose anlotinib significantly reduced tumor vessel density, whereas rising the dose of anlotinib did not improve the ability to prune the number of vessels. An effective low dose of anlotinib is sufficient to inhibit tumor growth with fewer side effects compared to higher doses (Fan et al. 2022 ). Recently, Yuan et al. demonstrated that low-dose anlotinib is a good antiangiogenic partner for combination therapy with ICIs in advanced NSCLC treatment. 40 patients with anlotinib administered at a dose of 8 and 10 mg were included in this study, but different doses were not stratified and analysed (Yuan et al. 2023 ). In our study, we enrolled widely varying doses of anlotinib, 8 mg and 12 mg to explore the effects of different doses of anlotinib on patients. The analysis confirmed longer PFS with ICIs in combination with 8 mg of anlotinib than that with 12 mg (8.7 vs 6.7 months; P = 0.016). Meanwhile, OS was longer in patients treated with ICIs + anlotinib (8 mg) than those treated with 12 mg, although the difference was not statistically significant (18.5 months vs 14.3 months, P = 0.065). This may be due to the fact that the relatively low dose of anlotinib resulted in a more sustained normalization of tumor vasculature. Besides, some studies have reported longer mPFS in patients without prior antiangiogenic therapy. Regretly, the data was not displayed in our study (P = 0.839). Addionally, male had longer PFS in combination immunotherapy with anlotinib compared to patients treated with anlotinib alone was mentioned in results (Sun et al. 2023 ). Similarly, in our findings, male was associated with better PFS and OS to combination therapy compared to female. In this study, the overall incidence of AEs with anlotinib in combination with ICIs was 68.0%. The most common AEs were hypertension, with a 24% incidence (≥ 3 grade = 3). 4 patients (8.0%) experienced grade 3 or higher AEs. In addition, our data showed that the incidence of AEs was higher with 12 mg of anlotinib plus ICIs than with 8 mg of anlotinib plus ICIs (82.6% vs 55.6%, P = 0.041), indicating that low-dose anlotinib combined with ICIs has lower AEs. It is worth mentioning that the incidence of AEs in this study was significantly lower than that reported by others. For example, Wang et al. (Wang et al. 2021 ) reported that the overall incidence of AEs was 85.0%. the incidence of grade 3–4 treatment-related AEs was about 40.0%. Zhai et al. (Zhai et al. 2020 ) found that the most common AEs were hypertension (45.5%),and the incidence of grade 3–4 hypertension was 9.1%. Our study also has some limitations. First, this is a retrospective analysis from a small sample of a single center, and bias is inevitable. Therefore, further large-scale prospective studies are needed to confirm our findings, which would benefit patients using anlotinib combination immunotherapy. Second, PD-L1 expression is considered a biomarker for treatment with anti-PD-1/PD-L1 drugs, but the levels of PD-L1 in patients was not available in this study (Mok et al. 2019 ; Li et al. 2019 ). Conclusion In summary, the efficacy and safety of 8 mg and 12 mg of anlotinib in combination with ICIs in patients with advanced NSCLC were explored. Patients with advanced NSCLC treated with the combination of 8 mg of anlotinib plus ICIs had better efficacy and lower toxicity. Therefore, our results add to the growing body of evidence supporting the benefits of combining immunotherapy with low-dose anlotinib. Declarations Author Contributions JW and TT conceptualized and supervised the project; TT, SY and JJ carried out the study and interpreted the results; TT and SY drafted the initial version of the manuscript; WC, JJ and MC searched the literature and collected data; JW and QX modified the revised manuscript; All authors read and approved the manuscript. Funding This study was supported by Health Commission of Anhui Province (AHWJ2023BAa10001). Data availability statement The data presented in this study are available on request from the corresponding author. The data are not publicly available due to a privacy issue from the patients. No datasets were generated or analysed during the current study. Conflicts of interest The authors declare no conflict of interest. Informed consent statement Informed consent was waived owing to the retrospective nature of the analyses. Ethics Approval This study was conducted in accordance with the Declaration of Helsinki and received approval from the Ethic Committee of The First Affiliated Hospital of Anhui Medical University (No. Quick-PJ2019-14-15). 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N Engl J Med 372(21):2018–2028 Han B, Li K, Wang Q, Zhang L, Shi J, Wang Z, Cheng Y, He J, Shi Y, Zhao Y, Yu H, Zhao Y, Chen W, Luo Y, Wu L, Wang X, Pirker R, Nan K, Jin F, Dong J, Li B, Sun Y (2018) Effect of anlotinib as a third-line or further treatment on overall survival of patients with advanced non-small cell lung cancer: The alter 0303 phase 3 randomized clinical trial. JAMA Oncol 4(11):1569–1575 Huang Y, Goel S, Duda DG, Fukumura D, Jain RK (2013) Vascular normalization as an emerging strategy to enhance cancer immunotherapy. Cancer Res 73(10):2943–2948 Huang Y, Yuan J, Righi E, Kamoun WS, Ancukiewicz M, Nezivar J, Santosuosso M, Martin JD, Martin MR, Vianello F, Leblanc P, Munn LL, Huang P, Duda DG, Fukumura D, Jain RK, Poznansky MC (2012) Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy. Proc Natl Acad Sci U S A 109(43):17561–17566 Kim JY, Lee KH, Kang J, Borcoman E, Saada-Bouzid E, Kronbichler A, Hong SH, de Rezende LFM, Ogino S, Keum N, Song M, Luchini C, van der Vliet HJ, Shin JI, Gamerith G (2019) Hyperprogressive disease during anti-pd-1 (pdcd1) / pd-l1 (cd274) therapy: A systematic review and meta-analysis. Cancers (Basel) 11(11) Li H, Xu Y, Wan B, Song Y, Zhan P, Hu Y, Zhang Q, Zhang F, Liu H, Li T, Sugimura H, Cappuzzo F, Lin D, Lv T, written on behalf of AMELCCG (2019) The clinicopathological and prognostic significance of pd-l1 expression assessed by immunohistochemistry in lung cancer: A meta-analysis of 50 studies with 11,383 patients. Transl Lung Cancer Res 8(4):429–449 Lin B, Song X, Yang D, Bai D, Yao Y, Lu N (2018) Anlotinib inhibits angiogenesis via suppressing the activation of vegfr2, pdgfrbeta and fgfr1. Gene 654:77–86 Liu S, Qin T, Liu Z, Wang J, Jia Y, Feng Y, Gao Y, Li K (2020) Anlotinib alters tumor immune microenvironment by downregulating pd-l1 expression on vascular endothelial cells. Cell Death Dis 11(5):309 Manegold C, Dingemans AC, Gray JE, Nakagawa K, Nicolson M, Peters S, Reck M, Wu YL, Brustugun OT, Crino L, Felip E, Fennell D, Garrido P, Huber RM, Marabelle A, Moniuszko M, Mornex F, Novello S, Papotti M, Perol M, Smit EF, Syrigos K, van Meerbeeck JP, van Zandwijk N, Yang JC, Zhou C, Vokes E (2017) The potential of combined immunotherapy and antiangiogenesis for the synergistic treatment of advanced nsclc. J Thorac Oncol 12(2):194–207 Miller KD, Nogueira L, Mariotto AB, Rowland JH, Yabroff KR, Alfano CM, Jemal A, Kramer JL, Siegel RL (2019) Cancer treatment and survivorship statistics, 2019. CA Cancer J Clin 69(5):363–385 Mok TSK, Wu YL, Kudaba I, Kowalski DM, Cho BC, Turna HZ, Castro G Jr., Srimuninnimit V, Laktionov KK, Bondarenko I, Kubota K, Lubiniecki GM, Zhang J, Kush D, Lopes G, Investigators K- (2019) Pembrolizumab versus chemotherapy for previously untreated, pd-l1-expressing, locally advanced or metastatic non-small-cell lung cancer (keynote-042): A randomised, open-label, controlled, phase 3 trial. Lancet 393(10183):1819–1830 Shen G, Zheng F, Ren D, Du F, Dong Q, Wang Z, Zhao F, Ahmad R, Zhao J (2018) Anlotinib: A novel multi-targeting tyrosine kinase inhibitor in clinical development. J Hematol Oncol 11(1):120 Sun L, Zhao Q, Wang Y, Wang Y, Zheng M, Ding X, Miao L (2023) Efficacy and safety of anlotinib-containing regimens in advanced non-small cell lung cancer: A real-world study. Int J Gen Med 16:4165–4179 Sun Y, Niu W, Du F, Du C, Li S, Wang J, Li L, Wang F, Hao Y, Li C, Chi Y (2016) Safety, pharmacokinetics, and antitumor properties of anlotinib, an oral multi-target tyrosine kinase inhibitor, in patients with advanced refractory solid tumors. J Hematol Oncol 9(1):105 Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F (2021) Global cancer statistics 2020: Globocan estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71(3):209–249 Syed YY (2018) Anlotinib: First global approval. Drugs 78(10):1057–1062 Van der Veldt AA, Lubberink M, Bahce I, Walraven M, de Boer MP, Greuter HN, Hendrikse NH, Eriksson J, Windhorst AD, Postmus PE, Verheul HM, Serne EH, Lammertsma AA, Smit EF (2012) Rapid decrease in delivery of chemotherapy to tumors after anti-vegf therapy: Implications for scheduling of anti-angiogenic drugs. Cancer Cell 21(1):82–91 Wang P, Fang X, Yin T, Tian H, Yu J, Teng F (2021) Efficacy and safety of anti-pd-1 plus anlotinib in patients with advanced non-small-cell lung cancer after previous systemic treatment failure-a retrospective study. Front Oncol 11:628124 Yang Y, Li L, Jiang Z, Wang B, Pan Z (2020) Anlotinib optimizes anti-tumor innate immunity to potentiate the therapeutic effect of pd-1 blockade in lung cancer. Cancer Immunol Immunother 69(12):2523–2532 Yuan S, Peng L, Liu Y, Till BG, Yan X, Zhang J, Zhu L, Wang H, Zhang S, Li H, Gao Q, Wang Z (2023) Low-dose anlotinib confers improved survival in combination with immune checkpoint inhibitor in advanced non-small cell lung cancer patients. Cancer Immunol Immunother 72(2):437–448 Zhai C, Zhang X, Ren L, You L, Pan Q, Pan H, Han W (2020) The efficacy and safety of anlotinib combined with pd-1 antibody for third-line or further-line treatment of patients with advanced non-small-cell lung cancer. Front Oncol 10:619010 Zhang X, Zeng L, Li Y, Xu Q, Yang H, Lizaso A, Mao X, Jin R, Zeng Y, Li Q, Wang J, Li Y, Zhang Y, Yang N (2021) Anlotinib combined with pd-1 blockade for the treatment of lung cancer: A real-world retrospective study in china. Cancer Immunol Immunother 70(9):2517–2528 Zhao S, Ren S, Jiang T, Zhu B, Li X, Zhao C, Jia Y, Shi J, Zhang L, Liu X, Qiao M, Chen X, Su C, Yu H, Zhou C, Zhang J, Camidge DR, Hirsch FR (2019) Low-dose apatinib optimizes tumor microenvironment and potentiates antitumor effect of pd-1/pd-l1 blockade in lung cancer. Cancer Immunol Res 7(4):630–643 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. 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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-4453491","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":307426259,"identity":"24db4c19-69b5-4a58-92bc-9fc97b1ffdfd","order_by":0,"name":"Tingfei Tan","email":"","orcid":"","institution":"Chinese Academy of Sciences","correspondingAuthor":false,"prefix":"","firstName":"Tingfei","middleName":"","lastName":"Tan","suffix":""},{"id":307426260,"identity":"c12c7d60-eeeb-4b1f-919e-44c149192cf9","order_by":1,"name":"Siyu Yuan","email":"","orcid":"","institution":"Anhui Medical University","correspondingAuthor":false,"prefix":"","firstName":"Siyu","middleName":"","lastName":"Yuan","suffix":""},{"id":307426261,"identity":"7b3512d3-76d3-4c95-999c-821d3e807761","order_by":2,"name":"Weiwei Chu","email":"","orcid":"","institution":"the First Affiliated Hospital of Anhui Medical University","correspondingAuthor":false,"prefix":"","firstName":"Weiwei","middleName":"","lastName":"Chu","suffix":""},{"id":307426262,"identity":"185d9ed0-0928-40f9-b93e-e0c56e9c08f8","order_by":3,"name":"Jiemei Jiang","email":"","orcid":"","institution":"the First Affiliated Hospital of Anhui Medical University","correspondingAuthor":false,"prefix":"","firstName":"Jiemei","middleName":"","lastName":"Jiang","suffix":""},{"id":307426263,"identity":"a31edf9f-a913-4d9e-b367-eb0dcc349374","order_by":4,"name":"Meiling Chen","email":"","orcid":"","institution":"Chinese Academy of Sciences","correspondingAuthor":false,"prefix":"","firstName":"Meiling","middleName":"","lastName":"Chen","suffix":""},{"id":307426264,"identity":"1aad3ce3-fb23-47c8-b849-92bd881f5be3","order_by":5,"name":"Quan Xia","email":"","orcid":"","institution":"the First Affiliated Hospital of Anhui Medical University","correspondingAuthor":false,"prefix":"","firstName":"Quan","middleName":"","lastName":"Xia","suffix":""},{"id":307426265,"identity":"718149f0-1680-42c4-953c-7227e7230509","order_by":6,"name":"Junping Wang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA5klEQVRIiWNgGAWjYHCCBCCWYGBgZmw48KFCQk6eeC3szI0PZ5yxMDZsINoyfvZmY962ikSGAwQUGhxgeCZduMMiT96ZsU1y5jyJBMYG5oePbuDXkiY984xEseFhxjaJj9sk8tgZ2IyNc/BoMQNp4W2TSNzYDLJlm0QxYwMPmzTRWqR550gkNhwgVst8Zkag9xuI0GJ/gCHZmveMROIGZkZgIB+TMDZsJuAXyQaexNu8O+oS5/cff3DgQ02dnDx788PH+LQwyL9JYGBsAAcdFDDjUw4G7AfAWuQbCKocBaNgFIyCkQoA/YtKu/gk8OYAAAAASUVORK5CYII=","orcid":"","institution":"Chinese Academy of Sciences","correspondingAuthor":true,"prefix":"","firstName":"Junping","middleName":"","lastName":"Wang","suffix":""}],"badges":[],"createdAt":"2024-05-21 08:55:27","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4453491/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4453491/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":57948770,"identity":"bfd421c6-8726-4212-8157-fcde31d33dbb","added_by":"auto","created_at":"2024-06-07 20:38:43","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":54622,"visible":true,"origin":"","legend":"\u003cp\u003eEfficacy of anlotinib in all patients. \u003cstrong\u003eA\u003c/strong\u003e The progression-free survival of all patients; \u003cstrong\u003eB\u003c/strong\u003ethe overall survival of all patients\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4453491/v1/a36568bb8a6a568b9a00274c.png"},{"id":57948771,"identity":"2cee14e5-3af1-46ad-86d3-070fc8da9884","added_by":"auto","created_at":"2024-06-07 20:38:43","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":43202,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier curves for progression-free survival \u003cstrong\u003eA\u003c/strong\u003e and overall survival \u003cstrong\u003eB\u003c/strong\u003e for different doses of anlotinib combined with Immune checkpoint inhibitors\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4453491/v1/ef7540975a9131d40a9b172b.png"},{"id":57949863,"identity":"ae4b871a-cb30-4279-a236-a7b79f55b2d4","added_by":"auto","created_at":"2024-06-07 20:54:46","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":946757,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4453491/v1/9098f4e4-bac5-4a20-8f57-6322352cbd1f.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Comparison of the efficacy and safety of different dose anlotinib in combination with immune checkpoint inhibitors for patients with advanced non-small cell lung cancer","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe Global Cancer Report 2020 showed that there were approximately 2.2\u0026nbsp;million new cases of lung cancer and 1.8\u0026nbsp;million deaths, accounting for approximately 11.4% of newly diagnosed cancers and 18.0% of deaths (Sung et al. \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). Lung cancer is the leading cause of cancer-related deaths globally, and non-small cell lung cancer (NSCLC) accounts for about 83% of lung cancer cases, most of which are locally advanced or metastatic at the time of diagnosis as well as have a poor prognosis (Miller et al. \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). The advent of immune checkpoint inhibitors (ICIs) has provided new strategies for the treatment of advanced NSCLC. A growing body of evidence suggests that immune checkpoint inhibitors, such as antibodies against programmed cell death-1 (PD-1) or its ligand programmed cell death-ligand 1 (PD-L1), significantly improve outcomes and prolong Overall survival (OS) in patients with advanced NSCLC (Brahmer et al. \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; Borghaei et al. \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e2015\u003c/span\u003e; Garassino et al. \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). However, not all patients benefit from ICIs alone. Some patients even over-progress after treatment with single ICIs (Kim et al. \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). Therefore, it is important to explore combination therapy regimens with ICIs for the benefit of patients with advanced NSCLC.\u003c/p\u003e \u003cp\u003eAngiogenesis plays a very important role in cancer progression (Claesson-Welsh and Welsh \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2013\u003c/span\u003e; Casanovas et al. \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e2005\u003c/span\u003e). Tumor growth and metastasis depend on abundant blood vessels, so blocking the pathways of tumor angiogenesis is an effective therapeutic strategy. Anlotinib is a tyrosine kinase inhibitor (TKI) that targets a wide range of tumor vascular and proliferative signaling receptors (Shen et al. \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e2018\u003c/span\u003e; Lin et al. \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e2018\u003c/span\u003e). Currently, anlotinib has been approved by China National Medical Products Administration for use in two types of advanced NSCLC patients who have progressed after chemotherapy (Syed \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e2018\u003c/span\u003e). Some studies have shown that the combination of anlotinib and ICIs has a synergistic effect. For patients with advanced NSCLC without epidermal growth factor receptor (EGFR) mutations, the combination of anlotinib and ICIs has good efficacy and tolerance as first-line therapy (Chu et al. \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). In second-line and beyond, anlotinib plus ICIs produced higher objective effectiveness rates (ORR) and longer progression-free survival (PFS) compared to ICIs monotherapy (Zhang et al. \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). These studies confirm that the combination of anlotinib with ICIs can improve the treatment outcome of NSCLC patients.\u003c/p\u003e \u003cp\u003eBased on the concept of a positive correlation between efficacy and dose, the 12 mg dose of anlotinib was frequently combined with ICIs in most studies (Sun et al. \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e2016\u003c/span\u003e). Interestingly, a series of studies have presented that using a lower dose results in a more homogeneous distribution of tumor vasculature compared to higher doses of antiangiogenic drugs (Huang et al. \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e2012\u003c/span\u003e; Van der Veldt et al. \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e2012\u003c/span\u003e; Huang et al. \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2013\u003c/span\u003e; Zhao et al. \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). Specifically, apatinib (a TKI drug similar to anlotinib) is better at normalizing tumor blood vessels when used at low doses. When combined with ICIs, the synergistic effect of low-dose apatinib was significantly higher than that of high dose (Zhao et al. \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e2019\u003c/span\u003e). In addition, low-dose apatinib better reprogrammed the tumor microenvironment from an immunosuppressive to an immunologically permissive microenvironment (Fukumura et al. \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2018\u003c/span\u003e). Therefore, the application of low-dose combination of antiangiogenic drugs and ICIs may have better antitumor synergistic effects than the high-dose combination group.\u003c/p\u003e \u003cp\u003eAnlotinib in combination with ICIs as a therapeutic strategy is becoming more widely in patients with NSCLC. However, the optimal combined dose of anlotinib remains to be determined. Here, we conducted this retrospective study to look at the status of anlotinib plus ICIs in the real world. Subgroups of results were also performed to compare the efficacy and safety of ICIs in combination with high dose (12mg) or low dose (8mg) of anlotinib. This study provides a reference for the clinical application of anlotinib combined with ICIs.\u003c/p\u003e"},{"header":"Patients and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design and Patients\u003c/h2\u003e \u003cp\u003ePatients diagnosed with advanced NSCLC who received 8 mg or 12 mg anlotinib in combination with ICIs as second-line or later therapy between February 2021 and August 2022 at the First Affiliated Hospital of Anhui Medical University in China were included. Further, the inclusion criteria were as follows: age\u0026thinsp;\u0026ge;\u0026thinsp;18 years; advanced stage (IIIB-IV) NSCLC were pathological identified; at least one measurable lesion; Eastern Cooperative Oncology Group (ECOG)\u0026thinsp;\u0026le;\u0026thinsp;3. While exclusion criteria were: mixed tumors of small cell and NSCLC ; active bleeding or serious systemic diseases; any adjust the dosage of anlotinib during treatment; any have not received follow-up information within two cycles after taking anlotinib. The clinical information system (donghua software) was performed to collect baseline characteristics, including gender, age, dose, ECOG score, pathological type, clinical stage, smoking history, gene mutation, treat line, hypertension, prior targeted therapy, prior anti-angiogenesis treatment, prior thoracic radiotherapy.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eTreatment\u003c/h2\u003e \u003cp\u003eAnlotinib was administered once daily (12 mg or 8 mg) on days 1\u0026ndash;14 of a 21-day cycle. The initial dose of anlotinib was determined by the oncologist according to the patients\u0026rsquo; status. ICIs was treated with PD-1 or PD-L1 antibodies including Camrelizumab (200 mg every 3 weeks) pembrolizumab ( 200mg every 3 weeks ), nivolumab (3 mg/kg every 2 weeks), sintilimab (200 mg every 3 weeks), toripalimab (240 mg every 3 weeks), or durvalumab (10mg/kg every 2 weeks). Follow-up data were collected up to October 30th, 2023. This study was approved by the First Affiliated Hospital of Anhui Medical University (No. Quick-PJ2019-14-15) and conducted according to the principles of the Declaration of Helsinki. Given the retrospective analysis, the requirement for individual consent was waived.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eEfficacy and Safety Assessments\u003c/h2\u003e \u003cp\u003eTherapeutic responses were assessed based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 every 2 cycles, defined as complete response (CR), partial response (PR), stable disease (SD) and progression disease (PD). PFS was characterized as the time between the date of the start of treatment with both anlotinib and ICIs, and the documented disease progression or death from any cause. Overall survival (OS) was defined as the time from initiation of treatment to death or last follow-up. ORR referred to the proportion of patients who have complete or a partial response to the therapy. Disease control rate (DCR) was defined as the proportion of patients with partial response (PR), complete response (CR), and stable disease (SD). Adverse reactions (AEs) were graded using the Common Terminology Criteria for Adverse Events version 5.0(CTCAE 5.0).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eThe baseline clinical features of all patients were summarized as categorical (percentage) and continuous data (mean and standard). Pearson Chi-square test was used to compare categorical variables and tumor responses between two groups. Comparison between groups for continuous variables were performed by an independent-sample t-test. The median PFS, OS, and 95% confidence interval (CI) were estimated using the Kaplan\u0026ndash;Meier method. Cox proportional hazards regression was carried out by the univariable and multivariable analyses and to calculate the hazard ratios (HR) with 95% CIs. All statistical analyses were performed using Statistical Products and Services Solutions, version 26 (SPSS 26.0).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eBaseline Clinical Characteristics of Patients\u003c/h2\u003e \u003cp\u003eA total of 50 patients were included in the analysis, of whom 31 (62.0%) were male and 19 (38.0%) were female. Among the patients, the mean age was 60.93\u0026thinsp;\u0026plusmn;\u0026thinsp;10.15. And there were 27 patients (54.0%) taking 8 mg of anlotinib, and 23 patients (46.0%) taking 12 mg of anlotinib. Besides, a total of 9 patients (18.0%) had a smoking history and 45 patients (90.0%) had an ECOG of 0\u0026ndash;1. The pathological diagnosis of the patient included squamous carcinoma (44.0%, 22/50) and adenocarcinoma (56.0%, 28/50). Of those, 25 (25.0%) patients received 3rd line or later line treatment with anlotinib. Overall, Stage IV disease was present in 42 patients (84.0%), gene mutations were identified in 15 patients (30.0%). Regarding treatment, 11 (22.0%) patients received prior targeted therapy. 18 patients (36.0%) were treated with prior anti-angiogenesis therapy. Additionally, 15 patients (30.0%) had previously undergone thoracic radiotherapy. The detailed baseline clinical characteristics of patients are listed in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\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\u003eBaseline Clinical Characteristics of Patients\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBasic Characteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo. of patients (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e31(62.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e19(38.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e60.93\u0026thinsp;\u0026plusmn;\u0026thinsp;10.15\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDoses of anlotinib\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e8mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e27(54.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e12mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e23(46.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eECOG score\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e0\u0026ndash;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e45(90.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5(10.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePathological type\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSquamous carcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e22(44.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdenocarcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e28(56.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical stage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;IV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8(16.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e42(84.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmoking history\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9(18.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e41(82.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGene mutation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e15(30.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e35(70.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTreat line\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e25(50.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e25(50.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrior targeted therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e11(22.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e39(78.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrior anti-angiogenesis treatment\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e18(36.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e32(64.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrior thoracic radiotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e15(30.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e35(70.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003e\u003cem\u003eECOG\u003c/em\u003e Eastern Cooperative Oncology Group\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eOverall Efficacy of Treatment\u003c/h2\u003e \u003cp\u003eIn the entire cohort, the median PFS (mPFS) of patients was 8.3 months (95% CI 6.3\u0026ndash;10.3), and the median OS (mOS) was 17.6 months (95% CI 16.5\u0026ndash;18.7) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA and Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB). Moreover, univariate analysis were performed to identify potential factors that associated with PFS and OS in all patients (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e), meanwhile the statistically significant factors (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05) were included into multivariate Cox regression analysis. Data revealed that gender (male vs female: HR\u0026thinsp;=\u0026thinsp;3.288, 95% CI 1.712\u0026ndash;6.313, P\u0026thinsp;=\u0026thinsp;0.000), and ICIs combined with different dose anlotinib (8mg vs 12mg: HR\u0026thinsp;=\u0026thinsp;2.110, 95% CI 1.154\u0026ndash;3.858, P\u0026thinsp;=\u0026thinsp;0.015) were identified as the independent influencing factors of PFS. Similarly, the independent factors influencing OS were gender (male vs female: HR\u0026thinsp;=\u0026thinsp;2.449, 95%CI 1.305\u0026ndash;4.597, P\u0026thinsp;=\u0026thinsp;0.005), and ICIs combined with anlotinib (8mg vs 12mg: HR\u0026thinsp;=\u0026thinsp;1.843, 95% CI 1.029-3.300, P\u0026thinsp;=\u0026thinsp;0.040) as well (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eUnivariate Cox Regression Analyses of PFS and OS\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\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=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003ePFS\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003eOS\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e96% CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender (male vs female)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3.169\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.667\u0026ndash;6.022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.000\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2.298\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.231\u0026ndash;4.289\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e0.009\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (\u0026lt;\u0026thinsp;65 years vs\u0026thinsp;\u0026ge;\u0026thinsp;65 years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.684\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.384\u0026ndash;1.219\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.198\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.823\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.454\u0026ndash;1.491\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.521\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eICIs combined with anlotinib (8mg vs 12mg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.033\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.120\u0026ndash;3.690\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.020\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.708\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.958\u0026ndash;3.044\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.069\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eECOG score (0\u0026ndash;1 vs\u0026thinsp;\u0026ge;\u0026thinsp;2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.866\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.728\u0026ndash;4.785\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.194\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.108\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.435\u0026ndash;2.823\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.830\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePathological type (Squamous carcinoma vs Adenocarcinoma)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.701\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.387\u0026ndash;1.270\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.241\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.703\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.386\u0026ndash;1.282\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.250\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical stage(\u0026lt;IV vs IV)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.565\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.260\u0026ndash;1.231\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.151\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.556\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.255\u0026ndash;1.215\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.141\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmoking history (yes vs no)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.944\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.468\u0026ndash;1.904\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.873\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.950\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.471\u0026ndash;1.915\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.885\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGene mutation (yes vs no)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.533\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.820\u0026ndash;2.867\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.181\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.200\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.640\u0026ndash;2.252\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.569\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTreat line (2 vs\u0026thinsp;\u0026ge;\u0026thinsp;3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.155\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.657\u0026ndash;2.031\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.617\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.114\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.634\u0026ndash;1.957\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.708\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrevious targeted therapy (yes vs no)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.972\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.979\u0026ndash;3.973\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.058\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.404\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.703\u0026ndash;2.804\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.336\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrevious anti-angiogenesis therapy (yes vs no)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.939\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.512\u0026ndash;1.722\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.839\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.944\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.524\u0026ndash;1.699\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.847\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrevious thoracic radiotherapy (yes vs no)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.630\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.320\u0026ndash;1.239\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.181\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.626\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.321\u0026ndash;1.223\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.171\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u003cem\u003eICIs\u003c/em\u003e Immune checkpoint inhibitors, \u003cem\u003eECOG\u003c/em\u003e Eastern Cooperative Oncology Group, \u003cem\u003eHR\u003c/em\u003e hazard ratio, \u003cem\u003eCI\u003c/em\u003e confidence interval, \u003cem\u003ePFS\u003c/em\u003e progression-free survival, \u003cem\u003eOS\u003c/em\u003e overall survival.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMultivariate Cox Regression Analysis of PFS and OS\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\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=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eVariable\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003ePFS\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003eOS\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eHR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e96% CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender (male vs female)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3.288\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.712\u0026ndash;6.313\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.000\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e2.449\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.305\u0026ndash;4.597\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e0.005\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eICIs combined with anlotinib (8mg vs 12mg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.110\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.154\u0026ndash;3.858\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.015\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.843\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.029-3.300\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u003cb\u003e0.040\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u003cem\u003eICIs\u003c/em\u003e Immune checkpoint inhibitors, \u003cem\u003eHR\u003c/em\u003e hazard ratio, \u003cem\u003eCI\u003c/em\u003e confidence interval, \u003cem\u003ePFS\u003c/em\u003e progression-free survival, \u003cem\u003eOS\u003c/em\u003e overall survival\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eEfficacy of low-dose anlotinib plus ICIs VS high-dose anlotinib plus ICIs\u003c/h2\u003e \u003cp\u003eBaseline characteristics were comparable between 8 mg of anlotinib plus ICIs and 12 mg of anlotinib plus ICIs (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Further data showed that patients receiving 8 mg of anlotinib\u0026thinsp;+\u0026thinsp;ICIs (n\u0026thinsp;=\u0026thinsp;27, 8.7 months) had significantly longer mPFS compared to those receiving 12 mg of anlotinib\u0026thinsp;+\u0026thinsp;ICIs (n\u0026thinsp;=\u0026thinsp;23, 6.7 months, p\u0026thinsp;=\u0026thinsp;0.016; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA). In addition, patients treated with 8 mg of anlotinib in combination with ICIs was associated with longer mOS than patients treated with 12 mg of anlotinib in combination with ICIs, although the difference was not statistically significant (18.5 months vs. 14.3 months, P\u0026thinsp;=\u0026thinsp;0.065; Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB). However, 8 mg of anlotinib plus ICIs and 12 mg of anlotinib plus ICIs were similar in terms of ORR (18.5% vs 13.0%, P\u0026thinsp;=\u0026thinsp;0.889) and DCR (85.2% vs 82.6%, P\u0026thinsp;=\u0026thinsp;1.000, Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). Overall, patients treated with low-dose anlotinib in combination with ICIs had longer survival than those treated with high-dose anlotinib.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of Baseline Characteristics Between 8 mg of anlotinib plus ICIs and 12 mg of anlotinib plus ICIs\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=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBasic Characteristics\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 mg of anlotinib plus ICIs (n\u0026thinsp;=\u0026thinsp;27)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 mg of anlotinib plus ICIs (n\u0026thinsp;=\u0026thinsp;23)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003et/X\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender\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\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e17(63.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e14(60.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.023\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.879\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10(37.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9(39.1)\u003c/p\u003e \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\u003eAge\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\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e63.43\u0026thinsp;\u0026plusmn;\u0026thinsp;7.95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e60.93\u0026thinsp;\u0026plusmn;\u0026thinsp;11.73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.869\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.389\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003edeviation\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\u003e\u0026lt;\u0026thinsp;65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e14(51.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e14(60.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.410\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.522\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge; 65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e13(48.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9(39.1)\u003c/p\u003e \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\u003eECOG score\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\u003e0\u0026ndash;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e23(85.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e22(95.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.573\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.449\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge; 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4(14.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1(4.3)\u003c/p\u003e \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\u003ePathological type\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\u003eSquamous carcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12(44.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10(56.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.005\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.945\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAdenocarcinoma\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e15(55.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e13(43.5)\u003c/p\u003e \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\u003eClinical 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=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026lt;IV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4(14.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4(17.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e23(85.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e19(82.6)\u003c/p\u003e \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\u003eSmoking history\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\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5(18.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4(17.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e22(81.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e19(82.6)\u003c/p\u003e \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\u003eGene mutation\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\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8(29.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7(30.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.951\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e19(70.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e16(69.6)\u003c/p\u003e \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\u003eTreat line\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\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e15(55.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10(43.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.725\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.395\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12(44.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e13(56.5)\u003c/p\u003e \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\u003ePrior targeted therapy\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\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6(22.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5(21.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.967\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e21(77.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e18(78.3)\u003c/p\u003e \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\u003ePrior anti-angiogenesis treatment\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\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e13(48.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5(21.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.76\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.053\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e14(51.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e18(78.3)\u003c/p\u003e \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\u003ePrior thoracic radiotherapy, n (%)\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\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e5(18.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e10(43.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.685\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.055\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e22(81.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e13(56.5)\u003c/p\u003e \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 \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003cem\u003eICIs\u003c/em\u003e Immune checkpoint inhibitors, \u003cem\u003eECOG\u003c/em\u003e Eastern Cooperative Oncology Group\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 \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eResponse of 8 mg of anlotinib plus ICIs and 12 mg of anlotinib plus ICIs\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\u003eResponse\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 mg of anlotinib plus ICIs (n\u0026thinsp;=\u0026thinsp;27)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 mg of anlotinib plus ICIs (n\u0026thinsp;=\u0026thinsp;23)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eX\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\" morerows=\"3\" rowspan=\"4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\" morerows=\"3\" rowspan=\"4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16\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=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eORR, (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5(18.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3(13.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.019\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.889\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDCR, (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23(85.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19(82.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e\u003cem\u003eICIs\u003c/em\u003e Immune checkpoint inhibitors, \u003cem\u003eCR\u003c/em\u003e complete response, \u003cem\u003ePR\u003c/em\u003e partial response, \u003cem\u003eSD\u003c/em\u003e stable disease, \u003cem\u003ePD\u003c/em\u003e progression disease, \u003cem\u003eORR\u003c/em\u003e Objective Response Rate, \u003cem\u003eDCR\u003c/em\u003e Disease control rate\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eSafety\u003c/h2\u003e \u003cp\u003eIn this analysis, treatment-related adverse events occurred in 34 of the 50 patients. The five most common adverse events (all grades) were hypertension (24.0%), hand-foot syndrome (16.0%), fatigue (16.0%), thyroid dysfunction (12.0%), and hoarseness (12.0%). The five most common\u0026thinsp;\u0026ge;\u0026thinsp;3 grade adverse events were hypertension (6.0%), hand-foot syndrome (2.0%). There were no treatment-related deaths or life-threatening adverse events. Furthermore, the most common adverse reaction was hypertension, followed by hand-foot syndrome and fatigue, regardless of whether ICIs was combined with 8 mg or 12 mg of anlotinib. Notably, compared with low-dose anlotinib plus ICIs, high-dose anlotinib plus ICIs resulted in an increased incidence of adverse events of all grades, although no new adverse reactions were observed (55.6% vs 82.6%, P\u0026thinsp;=\u0026thinsp;0.041). The incidence of grade 3 or above adverse reactions was similar between the two groups (13.0% vs 3.7%; P\u0026thinsp;=\u0026thinsp;0.49). The adverse reactions are listed in Table\u0026nbsp;\u003cspan refid=\"Tab6\" class=\"InternalRef\"\u003e6\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab6\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 6\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eAdverse events in patients treated with 8 mg of anlotinib plus ICIs and 12 mg of anlotinib plus ICIs\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\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=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eAdverse event\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eAll Patients (n\u0026thinsp;=\u0026thinsp;50)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003e8 mg of anlotinib plus ICIs (n\u0026thinsp;=\u0026thinsp;27)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003e12 mg of anlotinib plus ICIs (n\u0026thinsp;=\u0026thinsp;23)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAny grade (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;3 grade (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAny grade (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;3 grade (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eAny grade (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;3 grade (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypertension\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e12(24.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e3(6.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e6(22.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1(3.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e6(26.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2(8.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHand-foot syndrome\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8(16.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1(2.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2(7.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e6(26.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1(4.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFatigue\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8(16.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3(11.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e5(21.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGastrointestinal reaction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4(8.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1(3.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e3(13.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eThyroid dysfunction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6(12.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1(3.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e5(21.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProteinuria\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e4(8.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1(3.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e3(13.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHoarseness\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6(12.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2(7.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e4(17.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0(0.0)\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=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2(4.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1(3.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1(4.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLiver dysfunction\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3(6.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1(3.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e2(8.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHemoptysis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2(4.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e2(8.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypertriglyceridemia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1(2.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1(4.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0(0.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003e\u003cem\u003eICIs\u003c/em\u003e Immune checkpoint inhibitors\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe combination of antiangiogenic agents and ICIs has shown definite efficacy in a variety of solid tumors (Manegold et al. \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e2017\u003c/span\u003e). Similarly, the results of retrospective studies of anlotinib plus ICIs are promising treatment. In one hand, the mPFS for third-line treatment of NSCLC with anlotinib alone was 5.4 months and the mOS was 9.6 months (Han et al. \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2018\u003c/span\u003e). Surprisingly, the combination therapy in our study had mPFS, mOS of 8.3 months, 17.6 months, and 16% ORR respectively, which provided an additional 2.9 months of PFS and 8.0 months of OS benefit compared with anlotinib alone. In the other hand, favorable efficacy was obtained with combination therapy compared to PD-1 blockade alone. In the PD-1 blockade alone trial (KEYNOTE-001), ORR, mPFS, and mOS values were 19.4%, 3.7 months, and 12.0 months, respectively (Garon et al. \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e2015\u003c/span\u003e). The comparison of our data shows that the combination therapy is highly effective. Consistent with our conclusion, others have also confirmed that anlotinib in combination with ICIs has a favourable therapeutic effect in NSCLC (Wang et al. \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e2021\u003c/span\u003e). In terms of the mechanism, the combination of anlotinib and ICIs has a synergistic effect to regulate the tumor immune microenvironment, such as promoting the infiltration of natural killer cells, M1-like tumor-associated macrophages (TAMs), and dendritic cells, while decreasing the infiltration of M2-like TAMs (Yang et al. \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). In addition, anlotinib is able to inactivate the AKT pathway reducing PD-L1 expression on vascular endothelial cells, leading to an elevation in the CD8/FoxP3, thus activating the immune response (Liu et al. \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e2020\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAnti-angiogenic agents work by pruning tumor blood vessels and limiting nutrient supply to tumor cells (Eelen et al. \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2020\u003c/span\u003e). In vivo and in vitro studies demonstrated that relatively low-dose anlotinib significantly reduced tumor vessel density, whereas rising the dose of anlotinib did not improve the ability to prune the number of vessels. An effective low dose of anlotinib is sufficient to inhibit tumor growth with fewer side effects compared to higher doses (Fan et al. \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2022\u003c/span\u003e). Recently, Yuan et al. demonstrated that low-dose anlotinib is a good antiangiogenic partner for combination therapy with ICIs in advanced NSCLC treatment. 40 patients with anlotinib administered at a dose of 8 and 10 mg were included in this study, but different doses were not stratified and analysed (Yuan et al. \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). In our study, we enrolled widely varying doses of anlotinib, 8 mg and 12 mg to explore the effects of different doses of anlotinib on patients. The analysis confirmed longer PFS with ICIs in combination with 8 mg of anlotinib than that with 12 mg (8.7 vs 6.7 months; P\u0026thinsp;=\u0026thinsp;0.016). Meanwhile, OS was longer in patients treated with ICIs\u0026thinsp;+\u0026thinsp;anlotinib (8 mg) than those treated with 12 mg, although the difference was not statistically significant (18.5 months vs 14.3 months, P\u0026thinsp;=\u0026thinsp;0.065). This may be due to the fact that the relatively low dose of anlotinib resulted in a more sustained normalization of tumor vasculature. Besides, some studies have reported longer mPFS in patients without prior antiangiogenic therapy. Regretly, the data was not displayed in our study (P\u0026thinsp;=\u0026thinsp;0.839). Addionally, male had longer PFS in combination immunotherapy with anlotinib compared to patients treated with anlotinib alone was mentioned in results (Sun et al. \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2023\u003c/span\u003e). Similarly, in our findings, male was associated with better PFS and OS to combination therapy compared to female.\u003c/p\u003e \u003cp\u003eIn this study, the overall incidence of AEs with anlotinib in combination with ICIs was 68.0%. The most common AEs were hypertension, with a 24% incidence (\u0026ge;\u0026thinsp;3 grade\u0026thinsp;=\u0026thinsp;3). 4 patients (8.0%) experienced grade 3 or higher AEs. In addition, our data showed that the incidence of AEs was higher with 12 mg of anlotinib plus ICIs than with 8 mg of anlotinib plus ICIs (82.6% vs 55.6%, P\u0026thinsp;=\u0026thinsp;0.041), indicating that low-dose anlotinib combined with ICIs has lower AEs. It is worth mentioning that the incidence of AEs in this study was significantly lower than that reported by others. For example, Wang et al. (Wang et al. \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e2021\u003c/span\u003e) reported that the overall incidence of AEs was 85.0%. the incidence of grade 3\u0026ndash;4 treatment-related AEs was about 40.0%. Zhai et al. (Zhai et al. \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e2020\u003c/span\u003e) found that the most common AEs were hypertension (45.5%),and the incidence of grade 3\u0026ndash;4 hypertension was 9.1%. Our study also has some limitations. First, this is a retrospective analysis from a small sample of a single center, and bias is inevitable. Therefore, further large-scale prospective studies are needed to confirm our findings, which would benefit patients using anlotinib combination immunotherapy. Second, PD-L1 expression is considered a biomarker for treatment with anti-PD-1/PD-L1 drugs, but the levels of PD-L1 in patients was not available in this study (Mok et al. \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e2019\u003c/span\u003e; Li et al. \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2019\u003c/span\u003e).\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn summary, the efficacy and safety of 8 mg and 12 mg of anlotinib in combination with ICIs in patients with advanced NSCLC were explored. Patients with advanced NSCLC treated with the combination of 8 mg of anlotinib plus ICIs had better efficacy and lower toxicity. Therefore, our results add to the growing body of evidence supporting the benefits of combining immunotherapy with low-dose anlotinib.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eAuthor Contributions\u003c/h2\u003e\n\u003cp\u003eJW\u0026nbsp;and\u0026nbsp;TT conceptualized and supervised the project; TT, SY\u0026nbsp;and\u0026nbsp;JJ carried out the study and interpreted the results; TT\u0026nbsp;and\u0026nbsp;SY drafted the initial version of the manuscript; WC, JJ\u0026nbsp;and\u0026nbsp;MC searched the literature and collected data; JW\u0026nbsp;and QX\u0026nbsp;modified the revised manuscript; All authors read and approved the manuscript.\u003c/p\u003e\n\u003ch2\u003eFunding\u003c/h2\u003e\n\u003cp\u003eThis study was supported by Health Commission of Anhui Province (AHWJ2023BAa10001).\u003c/p\u003e\n\u003ch2\u003eData availability statement\u0026nbsp;\u003c/h2\u003e\n\u003cp\u003eThe data presented in this study are available on request from the corresponding author. The data are not publicly available due to a privacy issue from the patients. No datasets were generated or analysed during the current study.\u003c/p\u003e\n\u003ch2\u003e\u003cstrong\u003eConflicts of interest\u003c/strong\u003e\u0026nbsp;\u003c/h2\u003e\n\u003cp\u003eThe authors declare no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformed consent statement\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eInformed consent was waived owing to the retrospective nature of the analyses.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics Approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was conducted in accordance with the Declaration of Helsinki and received approval from \u0026nbsp;the Ethic Committee of The First Affiliated Hospital of Anhui Medical University (No. Quick-PJ2019-14-15).\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBorghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, Barlesi F, Kohlhaufl M, Arrieta O, Burgio MA, Fayette J, Lena H, Poddubskaya E, Gerber DE, Gettinger SN, Rudin CM, Rizvi N, Crino L, Blumenschein GR Jr., Antonia SJ, Dorange C, Harbison CT, Graf Finckenstein F, Brahmer JR (2015) Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. 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Cancer Immunol Res 7(4):630\u0026ndash;643\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":"advanced non-small cell lung cancer, low-dose anlotinib, immune checkpoint inhibitors, PD-1/PD-L1, combination therapy","lastPublishedDoi":"10.21203/rs.3.rs-4453491/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4453491/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose: \u003c/strong\u003eThe combination of anlotinib with immune checkpoint inhibitors (ICIs) has become a common treatment modality in clinical practice. However, the optimal dose of anlotinib to use remains unclear.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eWe collected patients with advanced non-small cell lung cancer (NSCLC) who received programmed cell death-1 (PD-1) or programmed cell death ligand 1 (PD-L1) blockade combined with different dose anlotinib as second-line or later line therapy. Subsequently, the efficacy and safety of the combination therapy as well as subgroup analyses of different doses of anlotinib were analyzed. Cox regression was performed to analyze significant factors correlated with progression-free survival (PFS) and overall survival (OS).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e A total of 50 eligible patients with NSCLC who received anlotinib combined with ICIs therapy were included, of which 27 received low-dose anlotinib (8 mg), and 23 were administered high-dose anlotinib (12 mg). The median PFS (mPFS) and the median OS (mOS) for all patients were 8.3 months (95% CI 6.3–10.3) and 17.6 months (95% CI 16.5–18.7), respectively. Subgroup analyses showed that patients treated with 8 mg of anlotinib plus ICIs had significantly longer mPFS than those treated with 12 mg of amlotinib plus ICIs (8.7 months vs 6.7 months; p=0.016). The overall incidence of adverse events (AEs) was 68.0%, and the most common AEs of all grades were hypertension. Meanwhile, the incidence of adverse events was higher for 12 mg of anlotinib plus ICIs than that of 8 mg of anlotinib plus ICIs(82.6% vs 55.6%, P = 0.041).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e Low-dose anlotinib in combination with ICIs for advanced NSCLC may be an effective and well-tolerated option.\u003c/p\u003e","manuscriptTitle":"Comparison of the efficacy and safety of different dose anlotinib in combination with immune checkpoint inhibitors for patients with advanced non-small cell lung cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-07 20:38:39","doi":"10.21203/rs.3.rs-4453491/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":"07db7708-3908-4a05-88fa-2b86d2e7d471","owner":[],"postedDate":"June 7th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-10-04T06:23:35+00:00","versionOfRecord":[],"versionCreatedAt":"2024-06-07 20:38:39","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4453491","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4453491","identity":"rs-4453491","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}