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Despite breakthroughs of immunotherapy synergistically combined with blockade of vascular endothelial growth factor receptor, several patients with advanced non‐small cell lung cancer (NSCLC) experience non‐response or followed relapse. Organized lymphoid aggregates, termed tertiary lymphoid structures (TLSs), are found to be associated with improved response to immunotherapy. Here, we explore the landscapes of TLSs in tumour tissues from a real‐world retrospective study. Our investigation showed that with a median follow‐up of 11.2 months, the ORR was 28.6% (18/63, 95% CI 17.9–41.3) and the median PFS was 6.1 (95% CI 5.5–6.6) months in NSCLC patients treated with PD‐1 blockade combined with anlotinib. By multiplex immunofluorescence (mIF) analysis, spatially, more TLSs and high CD20+ B‐cell ratio in TLSs were associated with higher ORR. High density of intratumoral CD8+ T cells showed better ORR and PFS. The numbers of CD8+ T cells with a distance within 20 μm and 20–50 μm between tumour cells were higher in responders than non‐responders. But responders had significantly higher TLSs within 20 μm rather than within 20–50 μm of tumour cells than non‐responders. The inflamed immunophenotyping occupied higher proportions in responders and was associated with better PFS. Besides, tumour cells in non‐responders were found more temporal cell‐in‐cell structures than responders, which could protect inner cells from T‐cell attacks. Taken together, landscape of TLSs and proximity architecture may imply superior responses to PD‐1 blockade combined with anlotinib for patients with advanced non‐small cell lung cancer. [ABSTRACT FROM AUTHOR]

Background: Epidermal growth factor receptor (EGFR) mutations are key drivers in a significant portion of non‐small‐cell lung cancer (NSCLC) patients. While third‐generation EGFR‐tyrosine kinase inhibitors (TKIs) such as osimertinib have demonstrated efficacy, the management of patients who continue to experience disease progression during treatment remains challenging. The emergence of drug resistance, including the development of secondary mutations, necessitates exploration of alternative treatment strategies. This study aims to evaluate and observe the efficacy and safety of almonertinib combined with anlotinib in patients after cancer progression during third‐generation EGFR‐TKI therapy. Methods: In this retrospective analysis, we included EGFR‐mutated NSCLC patients who were resistant to third‐generation EGFR‐TKIs. All patients were treated with almonertinib combined with anlotinib. The clinical characteristics, treatment history, clinical benefits, and adverse events of these patients were retrospectively collected. Results: A total of 16 eligible patients were included in the analysis. The results revealed that combination therapy with almonertinib and anlotinib was effective in this patient cohort. The overall response rate was 25% and the disease control rate was 93.75%. The 6 and 12 months of PFS rates were 92.9% (95% confidence interval [CI] 80.3%, 100.0%) and 84.4% (95% CI 66.6%, 100.0%), respectively. Moreover, this combination therapy was generally well‐tolerated, with manageable adverse events. Conclusion: Our retrospective analysis suggests that almonertinib and anlotinib combination therapy may represent a viable option for EGFR‐mutated NSCLC patients who have progressed on third‐generation EGFR‐TKIs, especially for those with posterior lines and no standard treatment options. Further investigation and larger clinical trials are warranted to validate these observations and refine treatment guidelines. [ABSTRACT FROM AUTHOR]

Currently, there is a lack of effective second-line and subsequent treatments for patients with extensive-stage small-cell lung cancer (ES-SCLC), and the establishment of a standardized treatment protocol is still underway. Considering the potential synergistic therapeutic effects of anti-angiogenic drugs and immune checkpoint inhibitors (ICIs), combination therapy could be a viable option for treating lung cancer. This research concentrates on assessing the efficacy and safety of anlotinib in combination with ICIs for the treatment of ES-SCLC. We undertook a retrospective analysis of patients with extensive-stage SCLC who received anlotinib in combination with ICIs as second-line and subsequent treatment at Zhejiang Cancer Hospital between April 2020 and April 2023. Survival rates were analyzed using the Kaplan-Meier method. Among the 43 patients who received combination therapy, there were no cases of complete response (CR), 16 patients who achieved partial response (PR), 21 patients who had stable disease (SD), and 6 patients who experienced disease progression (PD). This resulted in an overall response rate (ORR) of 37.2% (16/43) and a disease control rate (DCR) of 86.0% (34/43). The median progression-free survival (PFS) was 4.0 months (95% CI: 2.74-5.26), and the median overall survival (OS) time was 10 months (95% CI: 4.8-15.2). Cox multifactorial regression analysis disclosed that the performance score (PS) and the number of metastatic organs were independent factors influencing PFS in ES-SCLC (p<0.001). The combination therapy demonstrated acceptable toxicity, with a total grade 3/4 toxicity rate of 30.2%. The combination therapy showed a notable association with several adverse events, including hand-foot syndrome, hypertension, and fatigue, which were the most significant. Combining anlotinib with immune checkpoint inhibitors has demonstrated favorable efficacy and safety in the treatment of second-line and subsequent extensive-stage small-cell lung cancer. [ABSTRACT FROM AUTHOR]

Background: Extensive-stage small-cell lung cancer (ES-SCLC) is highly malignant, with early metastasis and high recurrence. Since therapeutic options are limited, ES-SCLC has a characteristically short survival period and extremely poor prognosis. A combination of immune checkpoint inhibitors (ICIs) and anti-angiogenic drugs can achieve promising efficacy and safety in patients with ES-SCLC as a second-line or subsequent treatment, extending survival to some extent. However, the clinical outcomes remain mostly unsatisfactory and are sometimes affected by treatment-related adverse events. Case presentation: A 57-year-old woman with ES-SCLC was administered a combination therapy of atezolizumab (a PD-L1 inhibitor) and anlotinib [an oral multi-targeted tyrosine kinase inhibitor (TKI)]. She survived for 22 months, with no disease progression during the 28 courses of therapy. Unexpectedly, despite having no history of asthma, the patient developed asthma while receiving this regimen. This is possibly related to T-cell activation and the tumor immune microenvironment, which induce allergic inflammation after PD-L1 blockade. Conclusions: This is the first report of an asthma-negative ES-SCLC patient who developed asthma after receiving atezolizumab plus anlotinib. Although this combination therapy may effectively extend survival in SCLC patients, asthmatic symptoms should be closely monitored. [ABSTRACT FROM AUTHOR]

Anlotinib is used for the treatment of advanced non‐small cell lung cancer; however, the emergence of drug resistance limits its clinical application. β‐sitosterol may also be used to treat lung cancer, but there have been no studies evaluating β‐sitosterol against anlotinib‐resistant lung cancer. The purpose of this study was to determine the mechanism by which β‐sitosterol enhances the sensitivity of lung cancer cells to anlotinib. A549 cells were treated with different concentrations of anlotinib to generate anlotinib‐resistant cells (A549/anlotinib cells). miR‐181a‐3p mimics were transfected into A549/anlotinib cells. A549 and A549/anlotinib cells were treated with β‐sitosterol at various concentrations. The Cell Counting Kit‐8 (CCK‐8) assay was used to measure cell proliferation. Apoptosis was assessed by flow cytometry. Real‐time quantitative PCR was used to measure the expression of miR‐181a‐3p. The interaction of miR‐181a‐3p with the H/ACA ribonucleoprotein assembly factor (SHQ1) was predicted using the miRDB and TargetScan Human databases and verified with a luciferase reporter assay. The expression of SHQ1, activating transcription factor 6 (ATF6), and glucose‐regulated protein 78 (GRP78) were measured by western blot analysis. β‐Sitosterol effectively suppressed A549/anlotinib cell proliferation and promoted apoptosis. SHQ1 is a downstream target of miR‐181a‐3p. The expression of miR‐181a‐3p was inhibited; however, SHQ1 expression was increased by β‐sitosterol treatment of A549/anlotinib cells. The inhibition of SHQ1, ATF6, and GRP78 protein expression by β‐sitosterol in A549/anlotinib cells was rescued by increased miR‐181a‐3p. β‐Sitosterol markedly promotes anlotinib‐resistant A549 cell apoptosis and inhibits cell proliferation by activating SHQ1/UPR signaling through miR‐181a‐3p inhibition. [ABSTRACT FROM AUTHOR]

To investigate the effects and mechanism of anlotinib intervention on glycolysis, proliferation, colony formation and migration of human lung cancer NCI-H226 cells, to provide reference for in vitro test of lung cancer. Human lung cancer NCI-H226 cells were divided into control group which is without intervention, experimental group involving 10, 20, 40 μmol/L anlotinib, and positive control group involving 20 μg/mL cisplatin. The cell counting kit-8 (CCK-8), 5-acetylene-2' deoxyuracil riboside (EdU) staining, plate clone formation, lactic acid detection kit, glucose detection kit, Transwell assay, RT-qPCR and Western blotting (WB) assays were used to detect proliferation viability, proliferation, colony-formation ability, lactic acid content, glucose consumption level, cell migration number and expression level of related factor levels. The proliferation activity, proliferation rate, clone formation rate, lactate content, glucose consumption level, N-cadherin, vimentin and fibronectin (FN) of NCI-H226 cells in control group, experimental group and positive drug group. There were significant differences in mRNA and protein expression levels between groups (P<0.05). The cell proliferation activity of 20 and 40 μmol/L anlotinib and positive drug groups was higher than that of control group (P<0.05). The cell proliferation rate, clone formation rate, lactate content, glucose consumption level and mRNA and protein expression levels of N-cadherin, vimentin and FN in the experimental group and the positive drug group were higher than those in the control group (P<0.05). Anlotinib can significantly inhibit glycolysis, proliferation, colony formation and migration of human lung cancer NCI-H226 cells. [ABSTRACT FROM AUTHOR]

Background: Albumin is believed to be associated with the prediction of various cancers. This retrospective cohort study aimed to explore the non-linear relationship between albumin level and overall survival (OS) in advanced non-small cell lung cancer (NSCLC) patients with anlotinib therapy, utilizing the Generalized additive model (GAM) approach. Specifically, we investigated the potential non-linear associations that might not be captured by conventional linear analyses. Methods: A retrospective cohort of 211 patients undergoing anlotinib treatment for advanced NSCLC was included in this study. A wide range of albumin levels was considered, and the GAM method was applied to account for potential confounding clinical variables and unveil the non-linear relationship between albumin and OS. Results: A non-linear relationship with inflection points of 40 g/L and 48 g/L was detected between albumin level and OS after adjusting for potential confounders. The hazard ratio (HR) of the left, middle and right of the inflection points were 0.95 (95 % confidence interval [CI], 0.87 to 1.04, p = 0.2819, n = 71), 0.75 (95 % CI, 0.64 to 0.89, p = 0.0007, n = 133) and 2.79 (95 % CI, 1.39 to 5.61, p = 0.0039, n = 7), respectively. The findings indicate a negative correlation between albumin level and OS when albumin level was between 40 g/L and 48 g/L. For every unit increase in albumin, there was a 25 % reduction in the risk of death. Subgroup analysis revealed that the negative relationship was enhanced with blood urea nitrogen (BUN) level increase and diminished with D-dimer increase. Conclusions: The relationship between albumin level and OS was non-linear. Albumin level is an independent prognostic factor for OS. In addition, BUN level and D-dimer level could modify the effect of albumin level on the risk of death in advanced NSCLC patients treated with anlotinib.

Abstract Objective Researches about the association between serum albumin-to-globulin ratio (AGR) and the prognosis of lung cancer are limited. We aimed to investigate the relationship between AGR and overall survival (OS) in patients with advanced non-small-cell lung cancer (NSCLC) treated with anlotinib. Methods A retrospective cohort study was conducted on 196 advanced NSCLC patients with anlotinib treatment between June 1, 2018 and June 1, 2021. The exposure was AGR, calculated by baseline serum albumin / (serum total protein - serum albumin). The outcome was OS, defined as the period from the date of initial treatment with anlotinib to death or the last follow-up. The univariate and multivariate linear regression models and generalized additive models (GAM) were used to analyze the relationship between AGR and OS. The Kaplan-Meier method was used to analyze the OS. Results After adjusting for potential confounders, a non-linear relationship was observed between AGR and OS, which had an inflection point of 1.24. The hazard ratio and the confidence intervals on the left and the right sides of the inflection point were 13.05 (0.52 to 327.64) and 0.20 (0.07 to 0.57), respectively. It suggested that AGR was positively associated with OS when AGR was larger than 1.24, for every 1 unit increase in AGR, the risk of death lowered approximately by 80%. Conclusions The relationship between AGR and the OS for advanced NSCLC patients with anlotinib is non-linear. AGR level is an independent protective factor for OS in advanced NSCLC patients who received anlotinib therapy.

Objective To investigate the efficacy and safety of Anlotinib combined with PD-1 blockades in patients with extensive-stage small-cell lung cancer （ES-SCLC）. Methods This study retrospectively analyzed the data of 36 patients with ES-SCLC who were treated with at least one previous systematic chemotherapy regimen. All the patients received Anlotinib plus PD-1 blockades therapy. Results Efficacy evaluation and safety analysis were conducted in all the patients. The best efficacy results showed objective response rate was 27.8% （95%CI: 14.2% ~ 45.2%）; disease control rate 80.6% （95%CI: 64.0% ~ 91.8%）. The PFS and OS of the 36 patients were 4.6 months （95%CI: 3.1 ~ 6.1） and 9.3 months （95%CI: 3.3 ~ 15.3）, respectively, indicating that overall adverse reactions were tolerate and controllable. Multivariate cox regression analysis for PFS indicated that ECOG performance status was the independent factor to predict PFS. Conclusion Anlotinib combined with PD-1 blockades regimen preliminarily demonstrates encouraging efficacy and tolerable safety for patients with ES-SCLC in realworld clinical practice. [ABSTRACT FROM AUTHOR]

Background: Anlotinib has demonstrated encouraging clinical outcomes in the treatment of lung cancer, soft tissue sarcoma and thyroid carcinoma. Several clinical studies have shown a relationship between anlotinib treatment and the occurrence of hyperlipidemia. The fundamental mechanisms, however, are still largely unclear. Here, the effect of anlotinib on lipid metabolism in an animal model and human cancer cells was evaluated and the role of lipid metabolism in the antitumor efficacy of anlotinib was investigated. Methods: The C57BL/6 J mouse model as well as A549 and H460 human lung cancer cell lines were used to examine the impact of anlotinib on lipid metabolism both in vivo and in vitro. Levels of triglycerides, high-density lipoprotein, low-density lipoprotein (LDL), and total cholesterol in serum or cell samples were determined using assay kits. The expression levels of crucial genes and proteins involved in lipid metabolism were measured by quantitative RT-PCR and Western blotting. Furthermore, exogenous LDL and knockdown of low-density lipoprotein receptor (LDLR) were used in H460 cells to investigate the relevance of lipid metabolism in the anticancer efficacy of anlotinib. Results: Anlotinib caused hyperlipidemia in C57BL/6 J mice, possibly by downregulating hepatic LDLR-mediated uptake of LDL cholesterol. AMP-activated protein kinase and mammalian target of rapamycin inhibition may also be involved. Additionally, anlotinib enhanced sterol response element binding protein 1/2 nuclear accumulation as well as upregulated LDLR expression in A549 and H460 cells, which may be attributable to intracellular lipid accumulation. Knockdown of LDLR reduced intracellular cholesterol content, but interestingly, anlotinib significantly improved intracellular cholesterol accumulation in LDLR-knockdown cells. Both exogenous LDL and LDLR knockdown decreased the sensitivity of cells to anlotinib. Conclusions: Anlotinib modulates host lipid metabolism through multiple pathways. Anlotinib also exerts a significant impact on lipid metabolism in cancer cells by regulating key transcription factors and metabolic enzymes. In addition, these findings suggest lipid metabolism is implicated in anlotinib sensitivity. [ABSTRACT FROM AUTHOR]

To investigate the effects of anlotinib on proliferation and apoptosis of A549 cells based on phosphatidylinositol 3-kinase (PI3K)/serine-threonine protein kinase (AKT) signaling pathway. A549 cells were divided into the control group, the experimental groups with different doses, the anlotinib group, the positive drug group, the inhibitor group and the activator group. The intervention time was 24 hours. The cell viability, cell morphology, the rate of proliferation, apoptosis and related protein expression levels were detected. The results showed that cell viability decreased after treatment with 20 μmol/L anlotinib. Compared with the control group, the cell growth of anlotinib group and positive drug group was inhibited, the cell proliferation rate, cysteinyl aspartate specific proteinase D1 (Cyclin D1) and the expression levels of p-PI3K and p-AKT decreased, and the number of apoptosis cells and the expression of cysteine aspartic protease-3 (Caspase-3) increased. The inhibitor enhanced these changes, while the activator had the opposite trend to the inhibitor. These results of this study indicate that anlotinib can significantly inhibit the proliferation and promote apoptosis of A549 cells, and its mechanism might be related to the inhibition of PI3K/AKT pathway signal transduction. The results of this study further illustrate the potential value of antilung cancer drugs and provide a new theoretical basis for the research and development of anti-lung cancer drugs. [ABSTRACT FROM AUTHOR]

Objective: Researches about the association between serum albumin-to-globulin ratio (AGR) and the prognosis of lung cancer are limited. We aimed to investigate the relationship between AGR and overall survival (OS) in patients with advanced non-small-cell lung cancer (NSCLC) treated with anlotinib. Methods: A retrospective cohort study was conducted on 196 advanced NSCLC patients with anlotinib treatment between June 1, 2018 and June 1, 2021. The exposure was AGR, calculated by baseline serum albumin / (serum total protein - serum albumin). The outcome was OS, defined as the period from the date of initial treatment with anlotinib to death or the last follow-up. The univariate and multivariate linear regression models and generalized additive models (GAM) were used to analyze the relationship between AGR and OS. The Kaplan-Meier method was used to analyze the OS. Results: After adjusting for potential confounders, a non-linear relationship was observed between AGR and OS, which had an inflection point of 1.24. The hazard ratio and the confidence intervals on the left and the right sides of the inflection point were 13.05 (0.52 to 327.64) and 0.20 (0.07 to 0.57), respectively. It suggested that AGR was positively associated with OS when AGR was larger than 1.24, for every 1 unit increase in AGR, the risk of death lowered approximately by 80%. Conclusions: The relationship between AGR and the OS for advanced NSCLC patients with anlotinib is non-linear. AGR level is an independent protective factor for OS in advanced NSCLC patients who received anlotinib therapy. [ABSTRACT FROM AUTHOR]

Objective: The histological conversion of lung adenocarcinoma (LUAD) into small-cell lung cancer (SCLC) is an important resistance mechanism for epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI)- resistant LUAD. Anlotinib has been recommended as the third-line treatment for SCLC patients. The efficacy of etoposide/platinum (EP) as the main treatment is very limited for patients with transformed SCLC. However, little is known about EP plus anlotinib for transformed SCLC. The present study retrospectively explored the clinical response to EP combined with anlotinib in patients with transformed SCLC from LUAD after EGFR-TKI failure. Methods: A total of 10 patients who underwent SCLC transformation from EGFR-TKI-resistant LUAD were retrospectively reviewed from September 1, 2019, to December 31, 2022, in three regional hospitals. All of the patients were treated with the combination regimen of EP and anlotinib for four to six cycles, followed by anlotinib maintenance therapy. The clinical efficacy indices including objective response rate (ORR), disease control rate (DCR), median progression-free survival (mPFS), median overall survival (mOS), and toxicities were evaluated. Results: The median time from EGFR-TKI treatment to SCLC conversion was 20.1 ± 2.76 months (17-24 months). Genetic examination after transformation showed that 90% of the patients retained their original EGFR gene mutations. Additional driver genes were found, including BRAF mutation (10%), PIK3CA mutation (20%), RB1 loss (50%), and TP53 mutation (60%). The ORR and DCR were 80% and 100%, respectively. The mPFS was 9.0 months (95% CI, 7.9-10.1 months), and the mOS was 14.0 months (95% CI, 12.0-15.9 months). Less than 10% of grade 3 toxicities were observed, and no grade 4 toxicity and death events were reported. Conclusion: The EP plus anlotinib regimen appears to be a promising and safe strategy in transformed SCLC patients after EGFR-TKI resistance, which warrants further investigation. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To probe into the clinical efficacy and safety of compound Kushen injection combined with anlotinib hydrochloride in the treatment of advanced lung cancer in elderly patients. METHODS: A total of 98 elderly patients with advanced lung cancer admitted into the hospital from Mar. 2018 to Sept. 2022 were selected to be divided into 51 cases in the treatment group (given Anlotinib hydrochloride capsules orally + compound Kushen injection for intravenous drip) and 47 cases in the control group (only given Anlotinib hydrochloride capsules orally). The clinical efficacy, Karnofsky performance scores (KPS) and incidences of adverse drug reactions were compared between two groups. RESULTS: One patient withdrew and 46 patients completed observation in the control group; three patients interrupted or withdrew for other reasons and 48 patients completed observation in the treatment group. After treatment, the effective remission rate was 19. 6% (9/46) and the disease control rate was 60. 9% (28/46) in the control group; the effective remission rate was 41. 7% (20/48) and the disease control rate was 83. 3% (40/48) in the treatment group, the differences between two groups were statistically significant (P<0. 05). According to the KPS score, compared with the same group before treatment, 11 cases had improved physical strength in the treatment group after treatment, 3 cases had improved physical strength in the control group, the differences between two groups were statistically significant (P<0. 05). The incidence of adverse drug reaction was 52. 1% (25/48) in the treatment group, lower than that of 71. 7% (33/46) in the control group, while the difference was not statistically significant (P = 0. 05). CONCLUSIONS: The application of compound Kushen injection combined with Anrotinib hydrochloride capsules on elderly patients with advanced lung cancer can improve clinical efficacy, reduce adverse drug reactions and improve patients’ quality of life. [ABSTRACT FROM AUTHOR]

Objective: To retrospectively analyze the efficacy and safety of osimertinib combined with anlotinib in the treatment of advanced non‐small‐cell lung cancer (NSCLC) after drug resistance, and to explore the related factors affecting the efficacy. Methods: The clinical data of 34 patients with advanced NSCLC who received osimertinib combined with anlotinib as three or more lines of treatment in the Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College from June 2019 to March 2022 were collected, and the therapeutic efficacy and safety were analyzed. Results: A total of 34 advanced NSCLC patients met the inclusion criteria. The objective response rate was 20.6%, the disease response rate was 88.2%, the median overall survival was 19.0 months, and the median progression‐free survival was 6.0 months. The common adverse events were mainly grade 1–2, and only three cases (11.1%) of adverse events were grade 3, including hypertension, proteinuria, and vomiting. No grade 4 or above adverse events were observed. Multivariate Cox regression analysis showed that the Eastern Cooperative Oncology Group Performance Status score and bone metastasis were independent prognostic factors for osimertinib combined with anlotinib as three or more lines of treatment in advanced NSCLC. Conclusions: Osimertinib combined with anlotinib as three or more lines of treatment in advanced NSCLC was effective and adverse events were tolerable. [ABSTRACT FROM AUTHOR]

Objectives: Treatments for advanced small‐cell lung cancer (SCLC) patients who are resistant to first‐line chemotherapy are limited. Given that antiangiogenic agents and immune‐checkpoint inhibitors (ICIs) can confer synergistic therapeutic benefits, combination therapy should be considered. We explored the efficacy and safety of combination therapy with anlotinib and programmed cell death protein 1 (PD‐1)/programmed cell death‐ligand 1 (PD‐L1) inhibitors as second‐line and subsequent therapy for advanced SCLC. Materials and Methods: We reviewed advanced SCLC patients at Shanghai Chest Hospital who had received anlotinib in combination with ICIs from November 2016 to November 2020 as second‐ and subsequent‐line treatment. Patients with advanced SCLC who had received paclitaxel monotherapy as second‐line treatment were included as the control group. Results: A total of 141 patients were included in the final analysis (40 in the combination therapy group and 101 in the paclitaxel monotherapy group). The median progression‐free survival (PFS) times for the combination therapy and paclitaxel monotherapy groups were 3.40 and 2.83 months (p = 0.022), respectively, while the median overall survival (OS) times for the combination therapy and paclitaxel monotherapy groups were 8.20 and 5.87 months (p = 0.048), respectively. Hypertension and hepatic dysfunction were the most pronounced adverse events of combination therapy and two patients changed regimens due to severe fatigue and anorexia. Conclusion: The combination of anlotinib and PD‐1/PD‐L1 blockade has promising efficacy and safety as a second‐line or subsequent therapy for SCLC. [ABSTRACT FROM AUTHOR]

Background: Lung cancer is a major public health issue and an enormous burden on society in China. Most lung cancers occur in elderly patients with non-small cell lung cancer (NSCLC), and many factors limit their treatment options. Chemotherapy-free therapy can avoid psychological fear, treatment pain, and adverse reactions caused by chemotherapy. Patients with non-small cell lung cancer with tumour protein p53 (TP53) gene mutations or Kirsten rat sarcoma viral oncogene homologue (KRAS) gene mutations tend to be more sensitive to anlotinib or programmed cell death protein 1 (PD-1) drugs. However, Kirsten rat sarcoma viral oncogene homologue is a proto-oncogene downstream of the epidermal growth factor receptor (EGFR) gene; therefore, if the Kirsten rat sarcoma viral oncogene homologue gene has an activating mutation, EGFR-targeted drug resistance may occur. Further studies are needed to explore whether patients with dual Kirsten rat sarcoma viral oncogene homologue and tumour protein p53 mutations can be treated with targeted immunotherapy without chemotherapy. Case presentation: A 74-year-old man was referred to the Lanzhou University Second Hospital due to chest tightness, shortness of breath, and weight loss for 2 months and was diagnosed with moderately to poorly differentiated adenocarcinoma. Laboratory examinations showed increased alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), cancer antigen (CA)-125, and CA199 levels, and gene sequencing indicated mutations in Kirsten rat sarcoma viral oncogene homologue and tumour protein p53. Immunohistochemical analysis showed positive PD-L1 and PD-1 expression. Peripheral blood immune checkpoint test using flow cytometry indicated that the PD-1 + CD8 levels were positive. After multi-disciplinary treatment, therapy with a combination of anlotinib and camrelizumab was initiated. Camrelizumab 200 mg was administered intravenously once every 3 weeks. Anlotinib 12 mg was administered orally daily before breakfast for 2 weeks with a week of rest in every cycle of 21 days. A reduction in alpha-fetoprotein, carcinoembryonic antigen, CA125, CA199, and CA724 levels was observed up to the first cycle, which decreased within the normal limits up to the second cycle and continued until the eighteenth cycle. The patient's chest tightness, shortness of breath, weight loss, and other symptoms significantly improved following treatment. Computed tomography imaging showed that the neoplastic lesion was dramatically reduced. The patient is currently being followed-up for more than 2 years to evaluate the duration of the response. Conclusion: Chemotherapy-free immunotherapy combined with targeted therapy is an effective treatment for advanced non-small cell lung cancer in elderly patients with Kirsten rat sarcoma viral oncogene homologue and tumour protein p53 mutations. Such therapies should be supported with further clinical studies with larger sample sizes. [ABSTRACT FROM AUTHOR]

Anlotinib is a small-molecule RTK inhibitor that has achieved certain results in further-line treatment, but many patients do not respond to this drug and lack effective methods for identification. Although radiomics has been widely used in lung cancer, very few studies have been conducted in the field of antiangiogenic drugs. This study aims to develop a new model to predict the efficacy of patients receiving anlotinib by combining pretreatment computed tomography (CT) radiomic characters with clinical characters, in order to assist precision medicine of pulmonary cancer. 254 patients from seven institutions were involved in the study. Lesions were selected according to the RECIST 1.1 criteria, and the corresponding radiomic features were obtained. We constructed prediction models based on clinical, NCE-CT, and CE-CT radiomic features, respectively, and evaluated the prediction performance of the models for training sets, internal validation sets, and external validation sets. In the RAD score only model, the area under curve(AUC) of the NCE-CT cohort was 0.740 (95% CI: 0.622, 0.857) for the training set, 0.711 (95% CI: 0.480, 0.942) for the internal validation set, and 0.633(95% CI: 0.479, 0.787) for the external validation set, while that of the CE-CT cohort was 0.815 (95% CI: 0.705, 0.926) for the training set, 0.771 (95% CI: 0.539, 1.000) for the internal validation set, and 0.701 (95% CI: 0.489, 0.913) for the external validation set. In the RAD score-combined model, the AUC of the NCE-CT cohort was 0.796 (95% CI: 0.691, 0.901) for the training set, 0.579 (95% CI: 0.309, 0.848) for the internal validation set, and 0.590 (95% CI: 0.427, 0.753) for the external validation set, while that of the CE-CT cohort was 0.902 (95% CI: 0.828, 0.977) for the training set, 0.865 (95% CI: 0.696, 1.000) for the internal validation set, and 0.837 (95% CI: 0.682, 0.992) for the external validation set. In conclusion, radiomics has accurate predictions for the efficacy of anlotinib. CE-CT-based radiomic models have the best predictive potential in predicting the efficacy of anlotinib, and model predictions become better when they are combined with clinical characteristics. [ABSTRACT FROM AUTHOR]

Background: This multicenter phase 1b/2 trial aimed to explore the maximum toler- ated dose (MTD), activity, and safety of anlotinib plus chemotherapy in patients with T790M-negative epidermal growth factor receptor (EGFR)-mutant advanced non- squamous non-small cell lung cancer (NSCLC) after resistance to first- or second- generation EGFR tyrosine kinase inhibitors (TKIs). Methods: In the phase 1b stage, patients received anlotinib (8/10/12 mg, days 1--14) combined with cisplatin (75 mg/m2, day 1) or carboplatin (AUC = 5, day 1) plus peme- trexed (500 mg/m2, day 1) for a 3-week cycle based on a 3 + 3 dose-escalation design. In the phase 2 single-arm stage, anlotinib was administered at MTD combined with plati- num plus pemetrexed for four cycles, followed by anlotinib maintenance therapy. The primary endpoint of the phase 2 stage was progression-free survival (PFS). Results: The study was prematurely terminated due to slow accrual after 19 patients had been enrolled between January 18, 2019, and March 21, 2021. The MTD of anloti- nib was 12 mg. The median PFS was 5.75 (95% confidence interval, 4.37--7.52) months. The objective response rate was 47.4% (95% confidence interval, 24.5%-- 71.1%). In the 12 mg group, seven (58.3%) patients experienced grade 3--4 treatment- related adverse events, and the most common ones were hypertension (6 [50.0%]), decreased platelet count (2 [16.7%]), and hypertriglyceridemia (1 [8.3%]). No treatment-related deaths occurred. Conclusion: Anlotinib plus platinum and pemetrexed showed promising antitumor activity with manageable toxicity in patients with T790M-negative EGFR-mutant advanced nonsquamous NSCLC after progression on first- or second-generation EGFR TKIs. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to evaluate the treatment response, survival profiles, prognostic factors and adverse events of anlotinib in treating advanced non-small cell lung cancer (NSCLC) patients.Materials and Methods: Totally, 158 advanced NSCLC patients were included in this retrospective study. All patients received anlotinib treatment until disease progression or intolerance: Administrated orally 12 mg/d for 2 weeks then discontinued for 1 week (3 weeks as a treatment cycle). Furthermore, treatment response, adverse events, and survivals were evaluated.Results: After 2 treatment cycles, no (0%) patients achieved complete response (CR), 7 (5.0%) patients achieved partial response (PR), 112 (80.0%) patients achieved standard deviation (SD), and 21 (15.0%) patients achieved progressive disease (PD), resulting in objective response rate (ORR) of 5.0% and disease control rate (DCR) of 85.0%. After 4 treatment cycles, no (0%) patients achieved CR, 3 (4.3%) patients achieved PR, 51 (74.0%) patients achieved SD, and 15 (21.7%) patients achieved PD, resulting in ORR of 4.3% and DCR of 78.3%. For survivals, the median progression-free (PFS) was 3.7 months (95% confidence interval [CI]: 2.7-4.7 months), and the median overall survival (OS) was 12.4 months (95% CI: 9.4-15.3 months). Subsequently, multivariate Cox's regression analyses illuminate that histological type (adenosquamous carcinoma vs. adenocarcinoma) and other mutation apart from epidermal growth factor receptor independently predicted shorter PFS; meanwhile, history of smoke and brain metastases independently predicted decreased OS. Regarding safety, most of the adverse events were at mild grade.Conclusion: Anlotinib displays good efficacy and well-tolerant safety profiles in the treatment of advanced NSCLC patients. [ABSTRACT FROM AUTHOR]

Objective: In the phase II ALTER-1202 (NCT03059797) trial, anlotinib significantly improved progression-free survival (PFS) and overall survival (OS) in patients with advanced small-cell lung cancer (SCLC) who underwent at least 2 previous chemotherapy cycles, when compared with a placebo group. To identify potential factors for predicting efficacy and prognosis with anlotinib treatment, we analyzed hematological indices at baseline and adverse events (AEs) over the course of anlotinib treatment. Methods: Data were collected from March 2017 to April 2019 from a randomized, double-blind, placebo-controlled, multicenter, phase II trial of anlotinib. Eligible patients were randomly assigned 2:1 to receive anlotinib or placebo until disease progression, intolerable toxicity, or withdrawal of consent. The patients received anlotinib (12 mg) or an analogue capsule (placebo) orally once daily for 14 days every 3 weeks. The hematological indices at baseline and AEs that occurred in the initial 2 treatment cycles were recorded. The Kaplan-Meier test and Cox regression model were used to assess survival differences. Results: A total of 82 patients (81 patients with complete data) were randomly assigned to receive anlotinib, with 38 receiving a placebo as a control. Multivariate analysis indicated that an elevated neutrophil to lymphocyte ratio > 7.75 and lactate dehydrogenase > 254.65 U/L at baseline were independent risk factors for PFS; basal elevated aspartate aminotransferase > 26.75 U/L, neuron specific enolase > 18.64 ng/mL, and fibrinogen > 4.645 g/L were independent risk factors for OS. During treatment, elevated γ glutamyltransferase and hypophosphatemia were independent predictors for a poor PFS, and elevated γ-glutamyl transferase and hypercholesterolemia were independent factors for OS. Conclusions: Our study preliminarily defined potential factors that affected the PFS and OS at baseline and during anlotinib treatment in patients with advanced SCLC. Our findings provide a basis for screening the dominant population and for dynamic efficacy monitoring with anlotinib therapy. [ABSTRACT FROM AUTHOR]

Small-cell lung cancer (SCLC) is a highly malignant, rapidly developing group of diseases with poor biological behavior. Most patients have extensive-stage SCLC (ES-SCLC) when they are first diagnosed. Standard chemotherapy is prone to relapse in a short period of time, and the patients' median overall survival (OS) can reach only 13 months when chemotherapy is given in combination with PD-L1 inhibitors. To date, no studies have verified the efficacy and safety of the composite treatment of ES-SCLC with penpulimab and anlotinib despite some recognized data and advantages related to this regimen. Penpulimab, a novel PD-1 inhibitor with an IgG1 subtype, has a structural modification of the Fc segment which can prevent the immune cells from being phagocytosed or killed and can steadily avoid tumor immune escape. This case report describes a 71-year-old man who had ES-SCLC for 7 years which progressed after receiving standard systemic chemotherapy combined with radiotherapy. The third-line treatment of four cycles of anlotinib and carilizumab was discontinued because of grade 2 immune-related pneumonia despite the efficacy being evaluated as stable disease. After maintaining 22 months of progression-free survival, the patient relapsed and switched to a safer regimen of penpulimab combined with anlotinib to continue the treatment for four cycles. Partial response evaluation was confirmed twice, and the patient remained in good general condition. The combination of penpulimab and anlotinib can positively regulate the therapeutic effect by simultaneously acting on the tumor microenvironment and promoting blood vessel normalization. In general, this case provides support for the successful possibility of a rechallenge with immune checkpoint inhibitors, the better clinical efficacy of cross-line therapy with anlotinib, and the drug safety of penpulimab, suggesting a beneficial therapy for the clinical treatment of ES-SCLC. [ABSTRACT FROM AUTHOR]

Abstract Background There is a lack of targeted therapeutic options for squamous cell lung cancer (SCC). Accelerated hypertension is an issue with many targeted therapies for lung cancer. This study aimed to analyze the efficacy of anlotinib, based on progression‐free survival (PFS) and overall survival (OS) in patients with SCC, stratified by hypertension and Eastern Cooperative Oncology Group (ECOG) score. Methods This was a post hoc analysis of a multicenter, double‐blind, phase III ALTER0303 randomized controlled trial. Only patients with SCC were included. The occurrence of hypertension during the study period was defined according to CTCAE 4.03. OS and PFS were the primary and secondary endpoints, respectively. The patients were stratified according to hypertension and ECOG score, respectively. Results The median PFS in the patients who developed hypertension was longer than in those who did not (7.2 (95% CI: 3.5–11.0) versus 3.2 (95% CI: 1.2–5.3) months, p = 0.001; HR (95% CI), 0.4 (0.2–0.8)). In the ECOG 0 patients, the median PFS in the patients who developed hypertension versus those who did not was 5.6 vs. 1.8 months, respectively (Figure 2(d)). In the ECOG 1 patients, the median PFS in the patients who developed hypertension versus those who did not was 7.0 (95% CI: 3.0–11.0) vs. 4.8 (95% CI: 1.2–8.5) months (p = 0.043). No statistically significant differences were found in OS in the stratified analyses. Conclusions The occurrence of hypertension might be a clinical indicator predicting the efficacy of third‐line anlotinib treatment in patients with SCC.

Xiaoting Pan,1,2,&ast; Wenhao Chen,2,3,&ast; Mengjun Nie,1,2 Yuanjie Liu,1,2 Zuopeng Xiao,1,2 Ying Zhang,1,2 Wei Zhang,1 Xi Zou1 1The Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, 210029, People’s Republic of China; 2No.1 Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 210023, People’s Republic of China; 3Jiangsu Cancer Hospital, Nanjing, Jiangsu, 210009, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xi ZouThe Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, 210029, People’s Republic of ChinaTel +86-18051983568Email zxvery@126.comBackground: Anlotinib is a vascular endothelial growth factor receptor tyrosine kinase inhibitor recommended for the treatment of advanced lung cancer patients after at least two previous systemic chemotherapies. Currently, many patients with lung cancer do not respond well to anlotinib treatment. Therefore, the aim of this metabolomic study was to determine the internal mechanism of anlotinib action at the molecular level and to identify the potential biomarkers and pathways associated with the therapeutic effects of anlotinib.Methods: A total of 20 male nude mice were randomly divided into 2 groups and treated with anlotinib or physiological saline. Ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry was performed to analyze the serum samples and determine the differential metabolites and pathways between anlotinib and control groups.Results: We observed significant differences between the anlotinib and control groups, and 13 endogenous differential metabolites and 5 potential metabolic pathways were identified. Glyoxylate and dicarboxylate metabolism, tryptophan metabolism, glycine, serine and threonine metabolism, phenylalanine metabolism and valine, leucine and isoleucine biosynthesis were the most important pathways regulated by anlotinib in vivo. Notably, these 5 differential pathways were highly associated with the TCA cycle, which is important in the proliferation and apoptosis of cancer cells.Conclusion: This serum metabolomic study revealed distinct metabolic profiles in lung cancer-bearing mice treated with anlotinib and identified differential metabolites and pathways between the anlotinib and control groups, which may provide new ideas for the clinical application of anlotinib.Keywords: anlotinib, lung cancer, LC-MS, differential metabolites, pathway

Rong Chen,1,2,* Fang-Ying Lu,1,2,* Bing Liu,1,2 Jingwen Huang,1,2 Min Zhou,1,2 Ranran Dai,1,2 Yi Guo1,2 1Department of Respiratory and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 2Institute of Respiratory Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yi Guo; Ranran DaiDepartment of Respiratory and Critical Care Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 197, Rui Jin 2nd Road, Shanghai, 200025, People’s Republic of ChinaTel +86 131 6622 1556; Tel +86 131 6622 1556Fax +86 21 6467 4301Email guoyi621@qq.com; drr11154@rjh.com.cnPurpose: Anlotinib is a multi-targeted tyrosine kinase inhibitor that inhibits tumor angiogenesis and cell proliferation. It is widely used as a third-line therapy for lung cancer. However, reliable prognostic biomarkers for predicting the efficacy of anlotinib are lacking. We conducted a retrospective study to investigate the prognostic value of serological inflammatory biomarkers in anlotinib treatment.Patients and Methods: Patients with advanced lung cancer treated with anlotinib monotherapy were enrolled. Cox regression was conducted to analyze the significant factors related to progression-free survival (PFS) and overall survival (OS). The objective response rate (ORR) was compared based on the median cut-off value of the significant inflammation index. Meanwhile, we created survival curves to compare the two groups and performed receiver operating characteristic curve analysis to assess the predictive ability of the inflammation index.Results: Among a total of 71 patients, the median PFS was 5.5 months and the median OS was 9.5 months. The ORR and disease control rate were 16.9% and 84.5%, respectively. According to univariate and multivariate analyses, absolute neutrophil count (ANC) was the only indicator associated with both PFS (hazard ratio [HR] =1.095, 95% confidence interval [CI] 1.030– 1.163, P=0.003) and OS (HR=1.057, 95% CI 1.003– 1.113, P=0.037). In the group with ANC ≥ 4.58, the ORR was relatively lower (8.1% vs 26.5%, P=0.057), but not statistically significant; PFS and OS were relatively shorter (median PFS 5.0 [95% CI 4.4– 9.6] vs 7.0 months [95% CI 4.4– 5.7], P=0.024 and median OS 7.3 [95% CI 4.7– 10.0] vs 17.6 months [95% CI 12.3– 22.9], P < 0.001). ANC had a relatively high discriminatory ability to predict 10-month survival, with an area under the curve of 0.729, sensitivity of 82.5%, and specificity of 67.7%.Conclusion: Elevated pre-treatment ANC was associated with a poor prognosis. Patients with lower peripheral blood levels of ANC might benefit from anlotinib.Keywords: lung cancer, anlotinib, absolute neutrophil count, progression-free survival, overall survival

Background: Anlotinib is a small molecular multi-targeting tyrosine kinase inhibitor. Growing evidence indicates that treatment efficacy, and toxicity varies considerably between individuals. Therefore, this study aimed to investigate the relationship between cytochrome P450 (CYP450) gene polymorphisms, drug concentrations, and their adverse reactions in anlotinib-treated patients with lung cancer. Methods: We enrolled 139 patients with lung cancer, treated with anlotinib. Twenty loci in the following five genes of the CYP450 family were genotyped: CYP450 family 3 subfamily A member 5 (CYP3A5), 3 subfamily A member 4 (CYP3A4), 2 subfamily C member 9 (CYP2C9), 2 subfamily C member 19 (CYP2C19), and 1 subfamily A member 2 (CYP1A2). Data on adverse reactions were collected from patients, and plasma anlotinib concentrations were measured. Results: There were significant variances in plasma trough concentration (3.95–52.88 ng/ml) and peak plasma concentration (11.53–42.8 ng/ml) following administration of 8 mg anlotinib. Additionally, there were significant differences in the plasma trough concentration (5.65–81.89 ng/ml) and peak plasma concentration (18.01–107.18 ng/ml) following administration of 12 mg anlotinib. Furthermore, for CYP2C19-rs3814637, the peak plasma concentrations of mutant allele T carriers (TT+CT) were significantly higher than those of wildtypes (CC). For CYP2C19-rs11568732, the peak plasma concentrations of the mutant allele G carriers (GT+GG) were significantly higher than those of the wild-type (TT). More importantly, the incidence rates of hypertension and hemoptysis (peripheral lung cancer) with TT+CT in rs3814637 and GT+GG in rs11568732 were significantly higher than those with CC and TT. Conclusions: The plasma trough and peak concentrations varied significantly for both 8 and 12 mg of anlotinib. Single-nucleotide polymorphisms in CYP2C19 are significantly associated with hypertension, hemoptysis, and anlotinib peak concentrations. Polymorphisms in CYP450 may explain inter-individual differences in anlotinib-related adverse reactions. [ABSTRACT FROM AUTHOR]

What is known and objective: Although osimertinib achieved convincing efficacy for patients with EGFR T790M‐positive non–small‐cell lung cancer (NSCLC) as second‐line treatment in the AURA3 clinical trials, patients developed drug resistance ultimately. Therefore, the present study was to investigate the clinical outcome and safety of osimertinib plus anlotinib for patients with previously treated EGFR T790M‐positive NSCLC. Methods: Designed as a retrospective study, this study consecutively included a total of 33 patients with advanced NSCLC who possessed a EGFR T790M‐positive mutation and progressed after the first‐line therapy. Eligible patients were treated with osimertinib plus anlotinib. Baseline characteristics of the patients were collected during hospitalization. Efficacy of the combination regimen was assessed with the change of target lesion using imaging evidence according to RECIST 1.1 criteria, and all the patients were followed up regularly. Adverse reactions were collected and documented during the treatment. Univariate analysis according to baseline characteristic subgroups was performed using log‐rank test, and multivariate analysis was carried out by Cox regression analysis. Results and discussion: The best overall response of the patients during osimertinib and anlotinib combination indicated that complete response was found in one patient, partial response was observed in 26 patients, stable disease was noted in 5 patients and progressive disease was reported in one patient. Therefore, objective response rate (ORR) of the combination regimen was 81.8% (95%CI: 64.5%–93.0%), and disease control rate (DCR) was 97.0% (95%CI: 84.2%–99.9%). Furthermore, the median progression‐free survival (PFS) of the 33 patients with NSCLC was 15.5 months (95%CI: 6.19–24.81). In addition, the median overall survival (OS) of the 33 patients with NSCLC was 23.8 months (95% CI: 17.67–29.93). Safety profile suggested that the most common adverse reactions of the patients with NSCLC who received anlotinib plus osimertinib were hypertension (63.6%), fatigue (57.6%), diarrhoea (48.5%%), dermal toxicity (39.4%) and proteinuria (33.3%). Interestingly, multivariate Cox regression analysis for PFS demonstrated that ECOG performance status was an independent factor to predict the PFS of the combination regimen. What is new and conclusion: Osimertinib plus anlotinib regimen preliminarily exhibited encouraging clinical outcomes and acceptable safety profile for patients with previously treated EGFR T790M‐positive NSCLC numerically. This conclusion should be validated in prospective clinical trials. [ABSTRACT FROM AUTHOR]

Summary: Background. Anlotinib hydrochloride is an oral small molecule inhibitor of multiple tyrosine kinases, and it has been approved as a third-line therapy for patients with advanced non-small-cell lung cancer (NSCLC) in China. This dose-exploration study was designed to investigate the feasibility of anlotinib in combination with other chemotherapy regimens in patients with nonsquamous NSCLC. Methods. This phase I study followed a 3 + 3 dose reduction design with three doses of anlotinib (12 mg, 10 mg, and 8 mg). Anlotinib was given at an initial dose of 12 mg with pemetrexed (500 mg/m2) plus cisplatin (75 mg/m2) or carboplatin (AUC = 5) on 21-day cycles for 4 cycles. The primary goal of the study was to identify the maximum tolerated dose (MTD), and secondary endpoints included progression-free survival (PFS) and overall survival (OS). Results. A total of eight participants were enrolled. Dose-limiting toxicities (DLTs) were observed in two patients (pts) at anlotinib 12 mg (grade 3 hand-foot syndrome and grade 3 appetite loss). No DLTs occurred with 10 mg anlotinib, and the MTD was 10 mg. Among seven evaluable pts, four achieved a confirmed partial response (PR), and three had stable disease (SD). With a median follow-up of 10.05 months, the median PFS was 7.00 months (95% CI: 2.76 to NE). Grade 3 treatment-related adverse events (TRAEs) included appetite loss (n = 2), hypertension (n = 2), thrombocytopenia (n = 1), diarrhea (n = 1) and hand-foot syndrome (n = 1). No grade 4 or grade 5 TRAEs were observed during the treatment. Conclusion. The feasible dose of anlotinib in combination with platinum/pemetrexed-based chemotherapy as a first-line regimen was 10 mg, which was well tolerated and showed promising antitumor activity in advanced nonsquamous NSCLC. [ABSTRACT FROM AUTHOR]

Abstract Background To study in vitro the effects of anlotinib combined with radiotherapy on the lung cancer H520 cell cycle and apoptosis. Methods The log growth period H520 cells were divided into the control group, anlotinib group (A group), radiotherapy group (RT group) and combined group (A + RT group). Cell cycle and apoptosis were detected by flow cytometry and changes in H520 cell cycle and apoptosis were analyzed in each group. Results Anlotinib was determined to significantly inhibit cell growth in all groups, both alone, or in combination with radiotherapy. After receiving corresponding treatments, the proportions of G2/M‐phase cells in the control group, A group, RT group and A + RT group were different, and statistically significant (F = 32.086, P

Background: Anlotinib is a small molecular multi-targeting tyrosine kinase inhibitor. Growing evidence indicates that treatment efficacy, and toxicity varies considerably between individuals. Therefore, this study aimed to investigate the relationship between cytochrome P450 (CYP450) gene polymorphisms, drug concentrations, and their adverse reactions in anlotinib-treated patients with lung cancer.Methods: We enrolled 139 patients with lung cancer, treated with anlotinib. Twenty loci in the following five genes of the CYP450 family were genotyped: CYP450 family 3 subfamily A member 5 (CYP3A5), 3 subfamily A member 4 (CYP3A4), 2 subfamily C member 9 (CYP2C9), 2 subfamily C member 19 (CYP2C19), and 1 subfamily A member 2 (CYP1A2). Data on adverse reactions were collected from patients, and plasma anlotinib concentrations were measured.Results: There were significant variances in plasma trough concentration (3.95–52.88 ng/ml) and peak plasma concentration (11.53–42.8 ng/ml) following administration of 8 mg anlotinib. Additionally, there were significant differences in the plasma trough concentration (5.65–81.89 ng/ml) and peak plasma concentration (18.01–107.18 ng/ml) following administration of 12 mg anlotinib. Furthermore, for CYP2C19-rs3814637, the peak plasma concentrations of mutant allele T carriers (TT+CT) were significantly higher than those of wildtypes (CC). For CYP2C19-rs11568732, the peak plasma concentrations of the mutant allele G carriers (GT+GG) were significantly higher than those of the wild-type (TT). More importantly, the incidence rates of hypertension and hemoptysis (peripheral lung cancer) with TT+CT in rs3814637 and GT+GG in rs11568732 were significantly higher than those with CC and TT.Conclusions: The plasma trough and peak concentrations varied significantly for both 8 and 12 mg of anlotinib. Single-nucleotide polymorphisms in CYP2C19 are significantly associated with hypertension, hemoptysis, and anlotinib peak concentrations. Polymorphisms in CYP450 may explain inter-individual differences in anlotinib-related adverse reactions.

Small-cell lung cancer (SCLC) is a highly malignant, rapidly developing group of diseases with poor biological behavior. Most patients have extensive-stage SCLC (ES-SCLC) when they are first diagnosed. Standard chemotherapy is prone to relapse in a short period of time, and the patients' median overall survival (OS) can reach only 13 months when chemotherapy is given in combination with PD-L1 inhibitors. To date, no studies have verified the efficacy and safety of the composite treatment of ES-SCLC with penpulimab and anlotinib despite some recognized data and advantages related to this regimen. Penpulimab, a novel PD-1 inhibitor with an IgG1 subtype, has a structural modification of the Fc segment which can prevent the immune cells from being phagocytosed or killed and can steadily avoid tumor immune escape. This case report describes a 71-year-old man who had ES-SCLC for 7 years which progressed after receiving standard systemic chemotherapy combined with radiotherapy. The third-line treatment of four cycles of anlotinib and carilizumab was discontinued because of grade 2 immune-related pneumonia despite the efficacy being evaluated as stable disease. After maintaining 22 months of progression-free survival, the patient relapsed and switched to a safer regimen of penpulimab combined with anlotinib to continue the treatment for four cycles. Partial response evaluation was confirmed twice, and the patient remained in good general condition. The combination of penpulimab and anlotinib can positively regulate the therapeutic effect by simultaneously acting on the tumor microenvironment and promoting blood vessel normalization. In general, this case provides support for the successful possibility of a rechallenge with immune checkpoint inhibitors, the better clinical efficacy of cross-line therapy with anlotinib, and the drug safety of penpulimab, suggesting a beneficial therapy for the clinical treatment of ES-SCLC. [ABSTRACT FROM AUTHOR]

Background: Existing evidence demonstrates that radiotherapy and antiangiogenic drugs have synergistic antitumour effects and may be a promising treatment option for patients with solid tumour. Thus, we performed a phase II trial to evaluate the efficacy and safety of whole-brain radiotherapy (WBRT) combined with anlotinib for multiple brain metastases (BMs) from non-small cell lung cancer (NSCLC) without targetable driver mutations. Methods: Patients with multiple BMs (⩾3) from NSCLC without targetable driver mutations who failed to respond to at least first-line chemotherapy were enrolled. Eligible patients received WBRT (30 Gy/10 f, 5 f/week) and anlotinib (12 mg/day, day 1-14 of 21 days per cycle, 2 cycles) until disease progression or treatment intolerance. The primary endpoint was intracranial objective response rate (iORR) and secondary endpoints included intracranial progression-free survival (iPFS), disease control rate (DCR), overall survival (OS), and safety. Results: Between April 2019 and March 2021, 21 patients were enrolled in the trial, of which 12 were aged ⩾60 years (57.1%), 13 were men (61.9%), 7 had an Eastern Cooperative Oncology Group Performance Status score of 0 to 1 (81.0%), 18 had adenocarcinoma (85.7%), and 11 had ⩾6 BMs (52.4%). Of the 21 evaluable patients, the iORR was 66.7% (1 complete response + 13 partial response [PR]), and 28.6% (7PR) had extracerebral lesions. The DCRs for intracerebral and extracerebral lesions were 90.5% and 81.0%, respectively. The iPFS and OS were 10.3 months (95% confidence interval [CI]: 0-24.8 months) and 13.4 months (95% CI: 0-27.9 months), respectively. The most frequently observed toxicities were loss of appetite (61.9%), hypertension (52.4%), fatigue (47.6%), diarrhoea (28.6%), vomiting (19.0%), dizziness (42.9%), and headache (33.3%). None of the patients developed grade 4 or higher grade adverse reactions. Conclusions: Anlotinib combined with WBRT is effective and well tolerated in patients with multiple BMs (⩾3) from NSCLC without targetable driver mutations. Therefore, further validation studies are required. Clinical trial registration number: ChiCTR 1900027769 [ABSTRACT FROM AUTHOR]

Background and objective Primary lung squamous carcinoma that produces alpha-fetoprotein (AFP) is rare and only four related cases have been reported so far. The specific reasons for elevated serum level of AFP and effective treatment regimens for AFP-producing lung squamous carcinoma are not clear. This paper reports the diagnosis and treatment of AFP-producing lung squamous carcinoma so as to provide some references for similar cases in clinical practice. Methods The diagnosis and treatment of an AFP-producing lung squamous carcinoma patient admitted to the Shandong Cancer Hospital on October 23, 2020 was retrospectively analyzed, and literatures were reviewed. Results A 52-year-old male patient was diagnosed as T4N3M0 stage, IIIc right upper lobe lung squamous cell carcinoma with mediastinal lymph node metastasis and multiple metastases in the lung. The main tumor marker was abnormally increased serum AFP. After the rapid progression of two lines chemotherapy, the patient was given anlotinib combined with carrizumab as third-line treatment. The efficacy evaluation reached to partial response (PR) and stable disease (SD) after 2 and 4 cycles of treatment, respectively. The treatment regimen was replaced with albumin paclitaxel plus carrizumab due to gastrointestinal bleeding after the fifth cycle. The patient's condition was under continuous control. Conclusions The AFP-producing lung squamous carcinoma patient had a good response to anlotinib and immunotherapy in the case report, which may provide some guidances for the clinical practice and the research on AFP-producing lung squamous carcinoma. [ABSTRACT FROM AUTHOR]

Haoyue Hu,1,* Yanyang Liu,1,* Songtao Tan,1,* Xiao Xiao Xie,1 Jun He,1,2 Feng Luo,1 Li Wang1 1Lung Cancer Center, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan, People’s Republic of China; 2Department of Oncology, The Third Hospital of Mianyang (Sichuan Mental Health Center), Mianyang, Sichuan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Feng Luo; Li WangLung Cancer Center, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University, Chengdu, Sichuan, People’s Republic of ChinaEmail hxyyluofeng@sina.com; wangli37029192@sina.comBackground: With a high frequency of 30%, KRAS mutations in patients with non-small cell lung cancer (NSCLC) often lead to their poor response to most anti-cancer therapies. As a multi-target tyrosine kinase inhibitor, Anlotinib shows clinical efficacy against several types of cancer. However, its effects on KRAS mutant NSCLC and the underlying molecular mechanisms remain unclear.Materials and Methods: Cell counting Kit-8 assay, colony formation assay, flow cytometry analysis, wound healing scratch assay, Transwell assay and xenograft mouse model were used to evaluate the anti-cancer effects of Anlotinib. The potential molecular mechanisms were determined by immunohistochemistry (IHC) and Western blotting.Results: Anlotinib inhibited proliferation of KRAS mutant lung cancer cells and induced apoptosis in vitro. In addition, the migration and invasion abilities of these cells were also decreased after treatment with Anlotinib. It significantly suppressed tumor growth in vivo and prolonged the survival of the xenograft-bearing mice, which correlated to lower expression levels of Ki67 in the tumor tissues. Mechanistically, Anlotinib downregulated MEK and ERK as well as their phosphorylated forms in the KRAS mutant lung cancer cells.Conclusion: Anlotinib inhibits the growth of KRAS mutant lung cancer cells partly via the suppression of the MEK/ERK pathway. Our findings provide novel insights into treating recalcitrant KRAS mutated NSCLC.Keywords: Anlotinib, KRAS-mutated, lung cancer, signal pathways

Objective: The purpose of this study was to initially investigate the effect of previous antiangiogenic therapy (bevacizumab and endostatin) on the efficacy of anlotinib in patients with advanced or metastatic lung cancer (LC). Methods: We retrospectively collected the clinical data of patients with LC treated with anlotinib and divided them into group A (treated with anlotinib after the failure of previous antiangiogenic drugs and group B (no prior use of antiangiogenic drugs). We used propensity score matching (PSM) for confounding factors between the groups. Progression-free survival (PFS) and overall survival (OS) were also recorded. Results: A total of 160 patients were included in the analysis. The median OS in groups A and group B was 11.8 months and 16.1 months (P=0.120), whereas the median PFS was 3.1 months and 4.7 months (P=0.009), respectively. Moreover, the objective response rate (ORR) of the two groups was 9.6% and 10.4% (P=0.874), and the disease control rate (DCR) was 71.1% and 80.5% (P=0.165). After PSM (n=46), baseline characteristics were comparable between groups A and B. Furthermore, the median OS of the two groups was 14.6 months and 16.2 months (P=0.320), whereas the median PFS was 3.5 months and 4.5 months (P=0.040), respectively. Moreover, the ORR of the two groups were 13.0% and 10.9% (P=0.748), and the DCR were 78.3% and 82.6% (P=0.599), respectively. Conclusions: Previous antiangiogenic treatments may affect the PFS of patients who receive anlotinib later, but it might not affect the patient's ORR and OS. [ABSTRACT FROM AUTHOR]

Background. This study aimed to evaluate the efficacy and safety of anlotinib combined with S-1 as a third- or later-line treatment for patients with stage IV non-small cell lung cancer (NSCLC). Anlotinib was approved in 2018 by the Chinese Food and Drug Administration (FDA) as a third-line treatment for patients with refractory advanced NSCLC and is under study in the U.S. and Europe. Methods. Simon's phase II clinical trial design with an α error of 5% and a power β of 80% was used, anticipating a 10% objective response rate (ORR) of anlotinib and a 30% ORR of anlotinib combined with S-1; the required sample size was 29. A total of 29 patients were enrolled in the clinical trial. Patients were treated with anlotinib plus S-1 over a 21-day treatment course until disease progression or unacceptable toxic effects. If the efficacy was assessed as stable disease, partial response, or complete response after six cycles, anlotinib was maintained until disease progression or death. The primary endpoint was the objective response rate. Somatic mutations were not required for study enrollment. Results. The median follow-up time was 11.1 months. Objective responses were observed in 11 of 29 (37.9%) patients making up the intention-to-treat population, which reached the target primary endpoint of 30% ORR. The median overall and progression-free survival were 16.7 and 5.8 months, respectively. The most common grade 3 adverse events (AEs) were gastrointestinal, including nausea, vomiting and diarrhea, fatigue, and hypertension. No grade 4 treatment-related AEs or treatment-related deaths occurred. Conclusion. The combination of anlotinib with S-1 in the third- or later-line treatment of stage IV NSCLC shows promising antitumor activity and manageable toxicity in patients with NSCLC; phase III trials will be planned in the future. [ABSTRACT FROM AUTHOR]

A simple, efficient, and stable detection method of two‐dimensional liquid chromatography (2D‐LC) was established and validated to determine anlotinib in the human plasma. The 2D‐LC system comprises a first‐dimensional column (LC1), an intermediate transfer column, and a second‐dimensional column (LC2). With simple protein precipitation treatment, the samples were processed directly for detection. The analysis cycle time was completed within 9.50 min. For the anlotinib concentrations, the calibration curve was linear over the 5.00–320.00 ng/mL range. The intra‐day and inter‐day precision ranges were 0.77–6.22% and 1.92–4.26%, respectively, for anlotinib concentrations. The recoveries were in the range of 97.85–102.50%. A total of 135 plasma samples from 94 patients were analyzed by our method. The plasma concentrations of patients were in the range of 5.17–106.38 ng/mL, in which the female had a higher plasma concentration (6.44–106.38 ng/mL). The simultaneous application of dexamethasone can increase the anlotinib concentration in the plasma. In our clinical application, we found that the factors that affect the plasma concentration include the time and dose of the medication, gender, and drug interactions. The method appears to be sensitive, precise, selective, and suitable for determining the concentration of anlotinib in the plasma sample. [ABSTRACT FROM AUTHOR]

Background: The presence of pleural effusion is an independent predictor for poor survival in patients with small‐cell lung cancer (SCLC). The aim of this study was to assess the efficacy and safety of anlotinib in patients with SCLC and pleural effusion. Methods: This was a randomized, double‐blind, multicenter, phase II trial. Patients histologically diagnosed with SCLC and pleural effusion and had received at least two lines of chemotherapy were enrolled into the study. The patients received anlotinib 12 mg/day or a placebo. Results: The overall response rate (ORR) was 3.7% for anlotinib (n = 27) and 0% in the placebo group (n = 15) (p = 1.000). The disease control rate (DCR) of the anlotinib group (63.0%) was higher than that of the placebo group (0%, p < 0.0001). The median progression‐free survival (PFS) increased in the anlotinib group (2.8 months) compared to the placebo group (0.7 months, HR = 0.10, 95% CI: 0.03–0.28, p < 0.001). The median overall survival of the anlotinib group (6.5 months) was higher than that of the placebo group (2.8 months, HR = 0.52, 95% CI: 0.22–1.23, p = 0.1285). The incidence of any grade adverse events was 100% in both groups. The percentage of grade 3–4 adverse events in the anlotinib group was 44.4% (12/27) compared to 40.0% (6/15) in the placebo group. Hypertension (37.0%), fatigue (29.6%), and loss of appetite (29.6%) typically appeared in the anlotinib group. Conclusions: In this post hoc analysis, anlotinib was associated with improved PFS in patients with SCLC and baseline pleural effusion. However, additional studies with a large sample size are necessary to substantiate the current findings. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the therapeutic potential of tumor suppression and mechanism for different implantation modes of iodine-125 (I-125) seeds irradiation in a mice xenograft model, and its skeletal complications. A total of 24 mice carrying A549 lung tumor-derived xenografts were randomly assigned to four groups, including non-radioactive (sham) seeds implantation, I-125 seeds fractional implantation, I-125 seeds single implantation and I-125 seeds single implantation combined with anlotinib. Ki67 immunohistochemistry, TUNEL immunofluorescence and CD31 morphometric analysis were used to determine the proliferation index, rate of apoptotic cells and microvessel density, respectively. Additionally, the side effects on the skeletal system in mice treated with I-125 seeds implantation were evaluated by histomorphometric staining with tartrate-resistant acid phosphate (TRAP) and alkaline phosphatase (ALP) expression in femur, tartrate-resistant acid phosphatase 5b (TRACP-5b) and procollagen type I N-terminal propeptide (PINP) levels in serum were evaluated by enzyme-linked immunosorbent assay (ELISA). The I-125 seeds single and fractionated implantation had similar therapeutic effects and complications when the total number of I-125 seeds was the same. A single implantation of I-125 seeds with or without anlotinib could analogously inhibit the tumor growth in xenografts mice, while the single implantation combined with anlotinib had more effective in tumor inhibition. The results of Ki67, TUNEL and CD31 staining confirmed an evident reduction in tumor cell proliferation and angiogenesis, as well as an increase in apoptosis. A relatively integrated bone metabolism was indicated after I-125 seeds single implantation with or without anlotinib, and the results were similar in I-125 seeds fractional implantation, including a reduction in the number of TRAP-positive cells and an increase in ALP expression level. Additionally, the serum TRACP-5b activity was decreased and the serum PINP concentration was increased following I-125 seeds implantation. Single and fractionated implantation pattern of I-125 radioactive seeds had similar therapeutic efficacy against tumor growth, while brachytherapy with I-125 seeds implantation may be an effective and safe treatment strategy for its potential protection against cancer treatment-induced bone loss. [ABSTRACT FROM AUTHOR]

Background: Acquired resistance development is a major challenge in the epidermal growth factor receptor‐tyrosine kinase inhibitor (EGFR–TKI) treatment of non–small cell lung cancer (NSCLC). Here, we investigated the potential effects of the concurrent use of anlotinib and EGFR‐TKI to overcome acquired resistance. Methods: We conducted a preclinical study to evaluate the antitumor effects of gefitinib + anlotinib in gefitinib‐resistant lung adenocarcinoma models in vitro and in vivo. We then investigated the treatment effect of EGFR–TKI + anlotinib therapy in 24 advanced EGFR‐mutant NSCLC patients after EGFR‐TKI acquired resistance between January 2018 and August 2020. Results: Anlotinib reversed gefitinib resistance in gefitinib‐resistant lung adenocarcinoma models by enhancing the antiproliferative and proapoptotic effects of gefitinib. The gefitinib + anlotinib treatment exerted a synergistic antitumor effect by downregulating the activation of VEGFR2 and downstream effectors, Akt and ERK. The EGFR–TKI + anlotinib therapy exhibited an objective response rate of 20.8% and a disease control rate of 95.8%. Median progression‐free survival (PFS) was 11.53 ± 2.41 months, but median overall survival was not reached. The median PFS was longer in patients experiencing gradual progression (13.30 ± 1.69 months) than in patients with dramatic progression (6.80 ± 1.75 months, p = 0.017). One grade 3 adverse event was noted (diarrhea, n = 2, 8.3%), and grade 4 or 5 adverse events were absent. Conclusions: EGFR–TKI combined with anlotinib demonstrated powerful antitumor activity in vitro and in vivo. Concurrent use of anlotinib overcomes acquired resistance to EGFR‐TKI in advanced EGFR‐mutant NSCLC patients. [ABSTRACT FROM AUTHOR]

45.7% of Chinese patients with advanced lung adenocarcinoma were reported to harbour sensitizing epidermal growth factor receptor (EGFR) mutations. Limited therapeutic options are left for non-small cell lung cancer (NSCLC) harbouring sensitizing EGFR mutations after failure of EGFR-tyrosine kinase inhibitor (TKI) therapy and chemotherapy, finding effective options for them is an unmet clinic need. Herein we reported a case that till January 12, 2021, an 82-year-old female with sensitizing EGFR-mutant advanced lung adenocarcinoma received a surprising progression-free survival (PFS) benefit of over 21 months from the combination therapy of pembrolizumab and anlotinib after her failure of treatments of osimertinib, chemotherapy and anlotinib-monotherapy. [ABSTRACT FROM AUTHOR]

ObjectiveThe purpose of this study was to initially investigate the effect of previous antiangiogenic therapy (bevacizumab and endostatin) on the efficacy of anlotinib in patients with advanced or metastatic lung cancer (LC).MethodsWe retrospectively collected the clinical data of patients with LC treated with anlotinib and divided them into group A (treated with anlotinib after the failure of previous antiangiogenic drugs and group B (no prior use of antiangiogenic drugs). We used propensity score matching (PSM) for confounding factors between the groups. Progression-free survival (PFS) and overall survival (OS) were also recorded.ResultsA total of 160 patients were included in the analysis. The median OS in groups A and group B was 11.8 months and 16.1 months (P=0.120), whereas the median PFS was 3.1 months and 4.7 months (P=0.009), respectively. Moreover, the objective response rate (ORR) of the two groups was 9.6% and 10.4% (P=0.874), and the disease control rate (DCR) was 71.1% and 80.5% (P=0.165).After PSM (n=46), baseline characteristics were comparable between groups A and B. Furthermore, the median OS of the two groups was 14.6 months and 16.2 months (P=0.320), whereas the median PFS was 3.5 months and 4.5 months (P=0.040), respectively. Moreover, the ORR of the two groups were 13.0% and 10.9% (P=0.748), and the DCR were 78.3% and 82.6% (P=0.599), respectively.ConclusionsPrevious antiangiogenic treatments may affect the PFS of patients who receive anlotinib later, but it might not affect the patient’s ORR and OS.

Lung cancer ranks as a leading cause of death. Although targeted therapies usually trigger profound initial patient responses, these effects are transient due to drug resistance and severe side effects. Xihuang Pill (XHW) is a popular Chinese medicine formula that might benefit cancer patients when used as a complementary therapy. However, its underlying mechanism when combined with anticancer drugs is not clearly understood. Here, we used an integrated strategy to reveal the regulatory properties of XHW in increasing the antitumor activity of anlotinib in lung cancer. We evaluated the anti-lung cancer effect of XHW combined with anlotinib in mice bearing Lewis lung carcinoma (LLC). We applied untargeted metabolomics to identify the differences metabolism and found that XHW improved the effects of anlotinib on lung cancer. The components and targets related to the effects of XHW treatment on lung cancer were obtained through network pharmacology. Then, by integrating the biologically active components of XHW and anlotinib as well as the treatment-responsive metabolites and their related targets, an interaction network was constructed to evaluate the combination therapy. Finally, important protein candidates for this response were verified by immunohistochemistry of tumor tissues. The results showed that XHW significantly improved the inhibitory effect of anlotinib on tumor growth in LLC-bearing mice. Additionally, 12 differentially-abundant metabolites were identified by untargeted metabolomics in the XHW/anlotinib group compared with the XHW or anlotinib groups, and they were mainly enriched in fatty acid metabolism, lipid metabolism and amino acid metabolism pathways. Anlotinib, 23 components in Shexiang, 2 components in Niuhuang, 30 components in Ruxiang and 60 components in Moyao work together to act on 30 targets to regulate hexadecanoic acid (also named palmitic acid), linoleic acid, lactosylceramide, adrenaline, arachidonic acid and lysoPC(18:1(9Z)). The results of immunohistochemistry showed that XHW combined with anlotinib reduced the expression of PDGFRA in tumors. Overall, the key metabolites of XHW that enhances the efficacy of anlotinib were regulated by a multicomponent and multitarget interaction network. Our results suggested that anlotinib combined with XHW may be a promising strategy for the treatment of lung cancer.

Background: This study evaluated the efficacy and safety of anlotinib combined with programmed cell death protein 1 (PD-1) blockade for the treatment of small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC). Patients and methods: SCLC (n = 28) and NSCLC (n = 177) patients who received treatment at Hunan Cancer Hospital between June 1, 2019, and July 1, 2020, were retrospectively analyzed. Progression-free survival (PFS) and treatment responses were compared among patients who received combination therapy of anlotinib plus PD-1 inhibitor, or monotherapy of either chemotherapy or PD-1 inhibitor. Independent prognostic factors were identified by Cox regression analysis. Results: Patients with relapsed SCLC who received anlotinib plus PD-1 inhibitor as a ≥ second-line therapy (n = 14) had a significantly longer PFS than those who received PD-1 inhibitor alone (n = 14, 5.0 vs. 3.0 months; P = 0.005). For patients with previously untreated wild-type NSCLC, the combination therapy in the first-line setting (n = 6) provided a marginally longer PFS than mono-chemotherapy (n = 6, 8.0 vs. 3.0 months; P = 0.075). For patients with relapsed NSCLC, the combination therapy in the ≥ second-line setting (n = 62) resulted in significantly higher objective response rate (19.3 vs. 5.0 vs. 2.4%; P = 0.013) and longer PFS (8.0 vs. 2.0 vs. 2.0 months; P <0.001) as compared to monotherapy of either chemotherapy (n = 41) or PD-1 inhibitor (n = 62). Anlotinib and PD-1 blockade combination therapy was an independent predictive factor of longer PFS (P <0.001). Conclusion: The combination of anlotinib and PD-1 inhibitor has promising efficacy and manageable toxicity as a second- or later-line treatment of relapsed NSCLC and possibly for relapsed SCLC. [ABSTRACT FROM AUTHOR]

Background: There is a lack of targeted therapeutic options for squamous cell lung cancer (SCC). Accelerated hypertension is an issue with many targeted therapies for lung cancer. This study aimed to analyze the efficacy of anlotinib, based on progression‐free survival (PFS) and overall survival (OS) in patients with SCC, stratified by hypertension and Eastern Cooperative Oncology Group (ECOG) score. Methods: This was a post hoc analysis of a multicenter, double‐blind, phase III ALTER0303 randomized controlled trial. Only patients with SCC were included. The occurrence of hypertension during the study period was defined according to CTCAE 4.03. OS and PFS were the primary and secondary endpoints, respectively. The patients were stratified according to hypertension and ECOG score, respectively. Results: The median PFS in the patients who developed hypertension was longer than in those who did not (7.2 (95% CI: 3.5–11.0) versus 3.2 (95% CI: 1.2–5.3) months, p = 0.001; HR (95% CI), 0.4 (0.2–0.8)). In the ECOG 0 patients, the median PFS in the patients who developed hypertension versus those who did not was 5.6 vs. 1.8 months, respectively (Figure 2(d)). In the ECOG 1 patients, the median PFS in the patients who developed hypertension versus those who did not was 7.0 (95% CI: 3.0–11.0) vs. 4.8 (95% CI: 1.2–8.5) months (p = 0.043). No statistically significant differences were found in OS in the stratified analyses. Conclusions: The occurrence of hypertension might be a clinical indicator predicting the efficacy of third‐line anlotinib treatment in patients with SCC. [ABSTRACT FROM AUTHOR]

Lung cancer ranks as a leading cause of death. Although targeted therapies usually trigger profound initial patient responses, these effects are transient due to drug resistance and severe side effects. Xihuang Pill (XHW) is a popular Chinese medicine formula that might benefit cancer patients when used as a complementary therapy. However, its underlying mechanism when combined with anticancer drugs is not clearly understood. Here, we used an integrated strategy to reveal the regulatory properties of XHW in increasing the antitumor activity of anlotinib in lung cancer. We evaluated the anti-lung cancer effect of XHW combined with anlotinib in mice bearing Lewis lung carcinoma (LLC). We applied untargeted metabolomics to identify the differences metabolism and found that XHW improved the effects of anlotinib on lung cancer. The components and targets related to the effects of XHW treatment on lung cancer were obtained through network pharmacology. Then, by integrating the biologically active components of XHW and anlotinib as well as the treatment-responsive metabolites and their related targets, an interaction network was constructed to evaluate the combination therapy. Finally, important protein candidates for this response were verified by immunohistochemistry of tumor tissues. The results showed that XHW significantly improved the inhibitory effect of anlotinib on tumor growth in LLC-bearing mice. Additionally, 12 differentially-abundant metabolites were identified by untargeted metabolomics in the XHW/anlotinib group compared with the XHW or anlotinib groups, and they were mainly enriched in fatty acid metabolism, lipid metabolism and amino acid metabolism pathways. Anlotinib, 23 components in Shexiang, 2 components in Niuhuang, 30 components in Ruxiang and 60 components in Moyao work together to act on 30 targets to regulate hexadecanoic acid (also named palmitic acid), linoleic acid, lactosylceramide, adrenaline, arachidonic acid and lysoPC(18:1(9Z)). The results of immunohistochemistry showed that XHW combined with anlotinib reduced the expression of PDGFRA in tumors. Overall, the key metabolites of XHW that enhances the efficacy of anlotinib were regulated by a multicomponent and multitarget interaction network. Our results suggested that anlotinib combined with XHW may be a promising strategy for the treatment of lung cancer. [ABSTRACT FROM AUTHOR]