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Background: This study evaluated the efficacy and safety of low‐dose anlotinib combined with immune checkpoint inhibitors as second‐line or later treatment for extensive‐stage small cell lung cancer (ES‐SCLC). Methods: The study included 42 patients with ES‐SCLC who were treated with low‐dose anlotinib combined with programmed cell death protein 1/programmed cell death‐ligand 1 inhibitors at Henan Cancer Hospital between March 2019 and August 2022. We retrospectively analyzed the efficacy and safety data for these patients. Indicators assessed included progression‐free survival (PFS), overall survival (OS), the overall response rate (ORR), the disease control rate (DCR), and adverse events (AEs). Prognostic factors were identified in univariate and multivariate analyses. Results: Median PFS was 11.0 months (95% CI: 7.868–14.132) and median OS was 17.3 months (95% CI: 11.517–23.083). The ORR was 28.5% and the DCR was 95.2%. Treatment‐related AEs were noted in 27 patients (64.3%), the most common of which was thyroid dysfunction (26.2%). Grade 3/4 treatment‐related AEs were observed in two patients (4.8%). Conclusions: A combination of low‐dose anlotinib and immune checkpoint inhibitors as second‐line or later treatment for ES‐SCLC may achieve longer PFS and OS and have manageable AEs. [ABSTRACT FROM AUTHOR]

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]

Objectives: To investigate the inhibitory effects of STM2457, which is a novel METTL3 (m6A writer) inhibitor, both as a monotherapy and in combination with anlotinib, in the treatment of oral squamous cell carcinoma (OSCC) both in vitro and in vivo. Materials and Methods: The efficacy of STM2457 or STM2457 plus anlotinib was evaluated using two OSCC cell lines by CCK8, transwell, colony formation, would‐healing, sphere formation, cell cycle, apoptosis assays, and nude mice tumor xenograft techniques. The molecular mechanism study was carried out by western blotting, qRT‐PCR, MeRIP‐qPCR, immunofluorescence, and immunohistochemistry. Results: STM2457 combined with anlotinib enhanced inhibition of cellular survival/proliferation and promotion of apoptosis in vitro. Moreover, this combinatorial approach exerted a notable reduction in stemness properties and EMT (epithelial‐mesenchymal transition) features of OSCC cells. Remarkably, in vivo studies validated the efficacy of the combination treatment. Mechanistically, our investigations revealed that the combined action of STM2457 and anlotinib exerted downregulatory effects on EGFR (epidermal growth factor receptor) expression in OSCC cells. Conclusions: The combination of STM2457 and anlotinib targeting EGFR exerted a multiple anti‐tumor effect. In near future, anlotinib combined with STM2457 may provide a novel insight for the treatment of OSCC. [ABSTRACT FROM AUTHOR]

Background: Immune‐checkpoint inhibitors are now used more commonly in combination than monotherapy as the first‐line choice in patients with unresectable advanced melanoma. Nevertheless, for cases that progressed after the initial combination therapy, the subsequent regimen option can be very difficult. Herein, we reported the efficacy and safety of a triple combination regimen in Chinese unresectable advanced melanoma patients who had poor responses to the first‐line immune therapy. Methods: We reviewed the clinical profiles of patients diagnosed with stage IIIC‐IV melanoma between June 1, 2020, and September 30, 2023. The patients who failed the prior immune therapies and received anti‐PD‐1 mono antibody plus interferon(IFN)‐alpha 1b and anlotinib hydrochloride as the second‐line therapy were enrolled in the retrospective analysis. Additionally, we examined the exhaustion of T‐cells using mIHC staining in available tumor samples. Results: Fifty‐five patients were included in this study. The median follow‐up period was 13.6 months. The objective response rate evaluated by the investigators was 9.1%(1CR, 4PR). The disease control rate was 47.3%. The median overall survival was 17.6 months, and the median progression‐free survival was 2.8 months. The adverse events rate of any grade was 100%. Grade 3 or 4 irAEs were observed in 29.1% of cases. Multiplex immunohistochemical staining revealed an increased trend of TIM3 expression on tumor‐infiltrating T cells in patients without objective response. Conclusion: PD‐1 monoclonal antibody plus interferon‐alpha 1b plus anlotinib showed acceptable tolerability and anticancer benefits in Chinese metastatic melanoma patients as a second‐line therapy. [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]

Background: Pancreatic ductal adenocarcinoma (PDAC) is in urgent need of a second‐line or later‐line treatment strategy. We aimed to analyze the efficacy and safety of additional anlotinib, specifically anlotinib in combination with immunotherapy, in patients with PDAC who have failed first‐line therapy. Methods: Patients with pathological diagnosis of PDAC were additionally treated with anlotinib, and some patients were treated with anti‐PD‐1 agents at the same time, which could be retrospectively analyzed. The efficacy and safety of additional anlotinib were evaluated. Results: A total of 23 patients were included. In patients treated with additional anlotinib, the overall median progression‐free survival (PFS) was 1.8 months and the median overall survival (OS) was 6.3 months, regardless of anti‐PD‐1 agents. Among patients receiving additional anlotinib in combination with anti‐PD‐1 agents, median PFS and OS were 1.8 and 6.5 months, respectively. Adverse events (AEs) were observed in 16 patients (69.6%). In patients treated with additional anlotinib, the majority of AEs were grade 1–3. Univariate analysis revealed that patients with baseline red blood cell distribution width (RDW) <14% treated with additional anlotinib plus anti‐PD‐1 agents had significantly longer OS than patients with baseline RDW ≥14% (p = 0.025). Patients with additional anlotinib plus anti‐PD‐1 agents as second‐line therapy had a longer OS than those treated as later‐line therapy (p = 0.012). Multivariate analysis showed that baseline RDW was the only independent risk factor for OS (p = 0.042). Conclusion: The combination of anlotinib and immunotherapy represents an effective add‐on therapy with tolerable AEs as second‐ or later‐line therapy in patients with PDAC, particularly in patients with baseline RDW <14%. [ABSTRACT FROM AUTHOR]

Background: The therapeutic potential of immune checkpoint blockade (ICB) extends across various cancers; however, its effectiveness in treating hepatocellular carcinoma (HCC) is frequently curtailed by both inherent and developed resistance. Objective: This research explored the effectiveness of integrating anlotinib (a broad‐spectrum tyrosine kinase inhibitor) with programmed death‐1 (PD‐1) blockade and offers mechanistic insights into more effective strategies for treating HCC. Methods: Using patient‐derived organotypic tissue spheroids and orthotopic HCC mouse models, we assessed the effectiveness of anlotinib combined with PD‐1 blockade. The impact on the tumour immune microenvironment and underlying mechanisms were assessed using time‐of‐flight mass cytometry, RNA sequencing, and proteomics across cell lines, mouse models, and HCC patient samples. Results: The combination of anlotinib with an anti‐PD‐1 antibody enhanced the immune response against HCC in preclinical models. Anlotinib remarkably suppressed the expression of transferrin receptor (TFRC) via the VEGFR2/AKT/HIF‐1α signaling axis. CD8+ T‐cell infiltration into the tumour microenvironment correlated with low expression of TFRC. Anlotinib additionally increased the levels of the chemokine CXCL14, crucial for attracting CD8+ T cells. CXCL14 emerged as a downstream effector of TFRC, exhibiting elevated expression following the silencing of TFRC. Importantly, low TFRC expression was also associated with a better prognosis, enhanced sensitivity to combination therapy, and a favourable response to anti‐PD‐1 therapy in patients with HCC. Conclusions: Our findings highlight anlotinib's potential to augment the efficacy of anti‐PD‐1 immunotherapy in HCC by targeting TFRC and enhancing CXCL14‐mediated CD8+ T‐cell infiltration. This study contributes to developing novel therapeutic strategies for HCC, emphasizing the role of precision medicine in oncology. Highlights: Synergistic effects of anlotinib and anti‐PD‐1 immunotherapy demonstrated in HCC preclinical models.Anlotinib inhibits TFRC expression via the VEGFR2/AKT/HIF‐1α pathway.CXCL14 upregulation via TFRC suppression boosts CD8+ T‐cell recruitment.TFRC emerges as a potential biomarker for evaluating prognosis and predicting response to anti‐PD‐1‐based therapies in advanced HCC patients. [ABSTRACT FROM AUTHOR]

Background: Besides the hallmark of H3K27M mutation, aberrant amplifications of receptor tyrosine kinases (RTKs) are commonly observed in diffuse midline glioma (DMG), a highly malignant brain tumor with dismal prognosis. Here, we intended to evaluate the efficacy and safety of a multitarget RTK inhibitor anlotinib in patients with H3K27M‐DMG. Methods: A total of 40 newly diagnosed H3K27M‐DMG patients including 15 with anlotinib and 25 without anlotinib treatment were retrospectively enrolled in this cohort. Progression‐free survival (PFS), overall survival (OS), and toxicities were assessed and compared. Results: The median PFS and OS of all patients in this cohort were 8.5 months (95% CI, 6.5–11.3) and 15.5 months (95% CI, 12.6–17.1), respectively. According to the Response Assessment in Neuro‐Oncology (RANO) criteria, the disease control rate in the anlotinib group [93.3%, 95% confidence interval (CI), 70.2–98.8] was significantly higher than those without anlotinib (64%, 95% CI: 40.5–79.8, p = 0.039). The median PFS of patients with and without anlotinib was 11.6 months (95% CI, 7.8–14.3) and 6.4 months (95% CI, 4.3–10.3), respectively. Both the median PFS and OS of DMG patients treated with anlotinib were longer than those without anlotinib in the infratentorial patients (PFS: 10.3 vs. 5.4 months, p = 0.006; OS: 16.6 vs. 8.7 months, p = 0.016). Multivariate analysis also indicated anlotinib (HR: 0.243, 95% CI: 0.066–0.896, p = 0.034) was an independent prognosticator for longer OS in the infratentorial subgroup. In addition, the adverse events of anlotinib administration were tolerable in the whole cohort. Conclusions: This study first reported that anlotinib combined with Stupp regimen is a safe and feasible regimen for newly diagnosed patients with H3K27M‐DMG. Further, anlotinib showed significant efficacy for H3K27M‐DMG located in the infratentorial region. [ABSTRACT FROM AUTHOR]

Objective: Previous studies had revealed that anlotinib had outstanding anti‐tumor efficacy on oral squamous cell carcinoma. However, the underlying mechanism is still unclear. Materials and Methods: Anlotinib resistant OSCC cells were established and analyzed by RNA‐sequencing. The correlations between SOD2 expression and anlotinib resistance were investigated in OSCC cells and PDX models. Functional assays were performed to verify the SOD2 expression and anlotinib resistance in OSCC cells. Results: Anlotinib resistant genes were enriched in the biological processes of mitochondrion organization and the gene pathway of reactive oxygen species. SOD2 expression level was positively correlated with the resistance of anlotinib in OSCC cells and PDX models. Higher SOD2 expression of OSCC cells was more resistant to anlotinib. Anlotinib induced ROS generation, apoptosis and mitochondrial damage in OSCC cells, which can be enhanced by SOD2 knockdown and decreased by SOD2 overexpression. Mitochondrial damage was identified as swelling and cristae disappearance morphology under TEM, decreased mitochondrial membrane potential and lower MFN2 expression. Conclusions: SOD2 may be capable of protecting mitochondria by downregulating ROS generation, which contributes to the resistance of anlotinib in OSCC cells. SOD2 can be utilized as a potential therapeutic target to improve the anti‐cancer efficacy of anlotinib in OSCC. [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]

Anlotinib, a multitarget tyrosine kinase inhibitor, can inhibit tumour angiogenesis proliferation, metastasis, promote vascular normalization, increase T cell and NK cell activity and infiltration, remodel tumour microenvironment and synergistic immune enhancement. Our study aimes to evaluate the efficacy of anlotinib in the treatment of advanced metastatic breast cancer (MBC) after multiple lines of therapy. Patients included were treated with anlotinib for advanced MBC in the Affiliated Cancer Hospital of Zhengzhou University from 1 January 2019 to 30 June 2023. The objective remission rate, disease‐free progression survival and adverse reactions were analysed. We compared and analysed the efficacy of anlotinib in the treatment of advanced metastatic breast cancer, which showed that ORR was 23.6% and DCR was 69.1%. The DCR of monotherapy was 66.7% and that of combination therapy was 69.6% in MBC patients. The combination therapy, combined with chemotherapy had the best effect (79.3%), combined with immunotherapy came second. In addition, the DCR (88.9%) was higher in MBC patients having received prior antiangiogenic therapy. According to the Kaplan–Meier (K‐M) survival estimate analysis, the mPFS was 4.17 months (95% CI, 1.758–6.582 months) in Her‐2 positive MBC patients, and 7.83 months (95% CI, 2.416–9.104) in Her‐2 negative MBC patients. The mPFS was 5.76 months (95% CI, 3.231–8.298 m) in HR positive MBC patients, 7.83 months (95% CI, 3.182–12.478 m) in TNBC patients. Fatigue (20.0%), hypertension (21.8%) and liver dysfunction (18.2%) were common adverse reactions, followed by bone marrow suppression (16.4%), anorexia (14.5%), hypothyroidism (14.5%) and diarrhoea (14.5%). Altogether, Anlotinib monotherapy or combination therapy provides a viable third (or above)‐line therapeutic strategy in patients with metastatic breast cancer. The adverse reactions of anlotinib are well tolerated and controllable. [ABSTRACT FROM AUTHOR]

Background: Patients with non‐small‐cell lung cancer (NSCLC) and uncommon EGFR alterations typically have worse treatment outcomes than patients with classically EGFR‐mutated NSCLC. This study aimed to investigate the efficacy and safety of PD‐1 blockade with sintilimab plus anti‐angiogenic treatment with anlotinib in patients with NSCLC harboring uncommon EGFR mutations. Methods: Patients with metastatic NSCLC harboring uncommon EGFR mutations after two previous treatments, including a platinum‐based chemotherapy regimen and a targeted treatment (or chemotherapy only for patients harboring EGFR ex20ins), received sintilimab combined with anlotinib. The primary endpoint was objective response rate (ORR). Results: At data cutoff (September 27, 2022), median follow‐up was 22.3 months (range, 1.2–37.6). Among 21 enrolled patients, 12 had EGFR ex20ins and nine had other uncommon EGFR mutations such as L861Q, G719A, and G709X. Overall, eight patients (38.1%) achieved an objective response, and 18 (85.7%) achieved disease control. Median (95% CI) progression‐free survival (PFS) was 7.0 (5.4–8.6) months, and median overall survival (OS) was 20.0 (15.6–24.4) months. The 12‐month PFS rate (95% CI) was 22.2% (7.4–42.0), and the 12‐month OS rate was 66.7% (42.5–82.5). Patients harboring EGFR ex20ins had similar ORR and PFS to those with other mutations. Six patients (28.6%) experienced grade 3 treatment‐related adverse events (TRAEs); hand‐foot syndrome was the most common grade 3 TRAE (2 patients; 9.5%). No grade ≥4 TRAEs were observed. Conclusions: The combination of sintilimab and anlotinib demonstrated durable efficacy and was generally well tolerated in patients with NSCLC and uncommon EGFR mutations who had received prior standard‐of‐care treatments. (ClinicalTrials.gov identifier: NCT04790409). [ABSTRACT FROM AUTHOR]

Aim: To study the safety and efficacy of anlotinib, a multitargeted tyrosine kinase inhibitor, in the treatment of advanced osteosarcoma (OSS) with metastases. Methods: We retrospectively studied patients with advanced OSS and metastases who received anlotinib treatment in our hospital from June 2018 to April 2020. All patients had received standard multimodal therapies, before taking anlotinib. Therapeutic doses of anlotinib were 12 mg for adults and 10 mg for children and adolescents once a day for 2 consecutive weeks, followed by a week of withdrawal. This 3‐week cycle of treatment was continued until the tumor progressed rapidly or the patients failed to tolerate the side effects. Adverse drug reactions were recorded, and therapeutic efficacy was evaluated based on progression‐free survival (PFS), disease control rate (DCR), overall survival (OS), and objective response rate (ORR). Results: The median PFS was 9.8 ±.9 months, and the 6‐ and 10‐month PFS rates were 73% and 33%, respectively. The median OS was 11.4 ±.6 months. No patients achieved complete response. After 6 months of treatment, the DCR and ORR were 80% and 13%, respectively. No drug‐related deaths or Grade 4 adverse events occurred in the patients. Five patients (33%) had Grade 3 adverse events. The most common drug‐related adverse events were hand‐food syndrome, fatigue, high blood pressure, anorexia, and pneumothorax. Conclusions: Anlotinib had a modest therapeutic effect in patients with advanced OSS after the failure of standard treatment. The adverse events were mostly tolerable or relieved after treatment. [ABSTRACT FROM AUTHOR]

The combination of immunotherapy and antiangiogenic agents for the treatment of refractory solid tumor has not been well investigated. Thus, our study aimed to evaluate the efficacy and safety of a new regimen of anlotinib plus PD‐1 inhibitor to treat refractory solid tumor. APICAL‐RST is an investigator‐initiated, open‐label, single‐arm, phase II trial in patients with heavily treated, refractory, metastatic solid tumor. Eligible patients experienced disease progression during prior therapy without further effective regimen. All patients received anlotinib and PD‐1 inhibitor. The primary endpoints were objective response and disease control rates. The secondary endpoints included the ratio of progression‐free survival 2 (PFS2)/PFS1, overall survival (OS) and safety. Forty‐one patients were recruited in our study; 9 patients achieved a confirmed partial response and 21 patients had stable disease. Objective response rate and disease control rate were 22.0% and 73.2% in the intention‐to‐treat cohort, and 24.3% and 81.1% in the efficacy‐evaluable cohort, respectively. A total of 63.4% (95% confidence interval [CI]: 46.9%‐77.4%) of the patients (26/41) presented PFS2/PFS1 >1.3. The median OS was 16.8 months (range: 8.23‐24.4), and the 12‐ and 36‐month OS rates were 62.8% and 28.9%, respectively. No significant association was observed between concomitant mutation and efficacy. Thirty‐one (75.6%) patients experienced at least one treatment‐related adverse event. The most common adverse events were hypothyroidism, hand‐foot syndrome and malaise. This phase II trial showed that anlotinib plus PD‐1 inhibitor exhibits favorable efficacy and tolerability in patients with refractory solid tumor. [ABSTRACT FROM AUTHOR]

Objectives: Acquired resistance represents a bottleneck to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment in lung cancer. Our study aimed to explore the efficacy of antiangiogenic‐based therapy in osimertinib‐resistant NSCLC patients and assess the efficacy of anlotinib in vitro study. Methods: Our multicenter study retrospectively collected 268 osimertinib‐resistant NSCLC patients with EGFR T790M mutation and explored the efficacy of anlotinib in patients and in vitro. Results: PFS was significantly longer in the antiangiogenic‐based therapy group than in the immunotherapy group (HR: 0.71, p = 0.050) and the chemotherapy group (HR: 0.28, p = 0.001). Both the ORR and DCR of the antiangiogenic‐based group were higher than the immunotherapy group and the chemotherapy group. Subgroup analysis showed a trend of more benefits from the anlotinib‐based therapy than the bevacizumab‐based therapy in terms of PFS (HR: 0.63, p = 0.087) and OS (HR: 0.52, p = 0.063). In vitro assays verified that anlotinib alone or combined with osimertinib exerted potent cytotoxicity to T790M‐mutant H1975 cell line with acquired osimertinib resistance. Conclusions: Our study suggested that antiangiogenic‐based therapy might improve PFS and OS in EGFR‐mutant NSCLC patients with acquired resistance to osimertinib. Moreover, anlotinib‐based therapy could be a promising effective treatment for this group of patients. [ABSTRACT FROM AUTHOR]

Despite the benefit with cancer immunotherapies in clinical implication, immunotherapeutic resistance occurred in many patients and the mechanism remains unknown. Increasing evidence has revealed that cell‐intrinsic programmed cell death ligand 1 (PD‐L1) may play a non‐negotiable part in immunotherapeutic resistance. Our present study aimed to elucidate the immune‐independent acquired resistance mechanism to PD‐L1 antibody. We found elevated PD‐L1 expression induced by PD‐L1 antibodies in cancer cell and vascular endothelial cells (VECs) with substantially acquired resistance to PD‐L1 antibodies. Moreover, proliferation of resistant cells was accelerated and the apoptosis was reduced in the absence of immune compared with parental cells. Subsequently, we confirmed that the activation of the PI3K/AKT pathway is involved in the upregulation of PD‐L1 expression. Finally, we found that low dose of anlotinib downregulated PD‐L1 expression only in VECs via inhibiting the PI3K/AKT pathway; however, the same effect was not observed in cancer cells. To sum up, our findings revealed that upregulation of PD‐L1 via activation of the PI3K/AKT signal pathway may promote acquired resistance to PD‐L1 antibodies in an immune‐independent manner. Significance: These findings provide new mechanisms of immunotherapeutic resistance and effective evidence of anlotinib combined with immunotherapy. [ABSTRACT FROM AUTHOR]

The objective of this study was to investigate the pharmacokinetic behavior of anlotinib in Chinese patients with malignant tumors using the population approach. A total of 407 anlotinib plasma concentrations from 16 patients were analyzed in this study. Anlotinib was administered orally 12 or 16 mg in the single‐dose phase and 12 mg once daily in the multiple‐dose phase. A population pharmacokinetic model was established using nonlinear mixed‐effects model method. The potential influence of demographic and pathophysiological factors on oral anlotinib pharmacokinetics was investigated in a covariate analysis. The final model was evaluated using goodness‐of‐fit plots, visual predictive check, and bootstrap methods. The pharmacokinetic profile of anlotinib was best described by a 1‐compartment model with first‐order absorption and first‐order elimination. The population estimates of the apparent total clearance, apparent volume of distribution, and absorption rate constant were 8.91 L/h, 1950 L, and 0.745/h, respectively. Body weight was identified as a significant covariate on apparent volume of distribution. Patients with low body weight tended to show higher exposure to anlotinib than those with high body weight. However, these differences were not clinically significant based on the simulations of the individual body weight effects. Taken together, this population pharmacokinetic model adequately described the pharmacokinetics of anlotinib in patients with malignant tumors and supports the same starting dose among them. [ABSTRACT FROM AUTHOR]

Synovial sarcoma is a highly malignant tumor that accounts for 10% of all soft tissue sarcomas. Primary pulmonary synovial sarcoma (PPSS) is extremely rare, and its prognosis is poor. A diagnosis is usually established after other primary lung malignancies or metastatic extrathoracic sarcomas have been excluded. Therefore, it is often misdiagnosed. In this study, we report the case of a 38‐year‐old woman who was misdiagnosed as having pleural mesothelioma and finally endured surgery to remove the tumor. The tumor showed SYT‐SSX fusion transcripts and was diagnosed as PPSS after combining histopathological and immunohistochemical analyses. Finally, we determined some biomarkers through whole‐exome sequencing (WES) to improve the diagnosis and treatment strategies. [ABSTRACT FROM AUTHOR]

Background: The prognosis of patients with small cell lung cancer (SCLC) and brain metastases (BM) was poor. This study aimed to explore the efficacy and safety of anlotinib as third‐line or above treatment in SCLC with BM. Methods: This was a subgroup analysis of the ALTER1202 trial, which was a randomized, placebo‐controlled trial aimed to evaluate the role of anlotinib as third‐line treatment or above in patients with SCLC. This study included patients with BM at baseline. The efficacy and safety outcomes included progression‐free survival (PFS), overall survival (OS), central nervous system (CNS), objective response rate (ORR), CNS disease control rate (DCR), time to CNS progression, and adverse events (AEs). Results: Twenty‐one and nine patients with BM were included in the anlotinib and placebo groups, respectively. The median PFS and OS were 3.8 months (95% confidence interval [CI]: 1.8–6.1) and 6.1 months (95% CI: 4.1–8.0) in the anlotinib group. Anlotinib was associated with a significant improvement in PFS (hazard ratio [HR] = 0.15, 95% CI: 0.04–0.51, p = 0.0005) and OS (HR = 0.26, 95% CI: 0.09–0.73, p = 0.0061) than placebo. Anlotinib significantly prolonged the time to CNS progression (p < 0.0001). The anlotinib group had a higher CNS DCR than placebo (95.2% vs. 22.2%, p = 0.0001). The most common grade 3 or higher AEs were increased lipase (19.0%), hypertension (14.3%), and hyponatremia (14.3%) in the anlotinib group. Conclusions: Anlotinib proved to have potential CNS activity and a manageable toxicity profile in patients with SCLC and BM, significantly delaying CNS progression. [ABSTRACT FROM AUTHOR]

Dynamic alterations of ctDNA associate with the therapeutic outcome in the advanced non-small cell lung cancer patients who received sintilimab plus anlotinib regime as 1st line therapy (B) Progression-free survival (PFS) enrichment for the high level of MSAF patients (MSAF-H) and low level of MSAF patients (MSAF-L). Furthermore, Kaplan-Meier curve analysis showed that the NSCLC patients with high MSAF received a median PFS of 836 days, while the patients with low MSAF received a median PFS of 322 days at BL ( I p i = .011; Figure 1C). Results suggested that the NSCLC patients with high MSAF received more PFS benefit than those with low MSAF the patients ( I p i = .029; Figure 2G). [Extracted from the article]

Patients with biliary tract cancer (BTC) were associated with poor prognosis and limited therapeutic options after first‐line therapy currently. In this study, we sought to evaluate the feasibility and tolerability of sintilimab plus anlotinib as the second‐line treatment for patients with advanced BTC. Eligible patients had histologically confirmed locally advanced unresectable or metastatic BTC and failed after the first‐line treatment were recruited. The primary endpoint was overall survival (OS). Simultaneously, association between clinical outcomes and genomic profiling and gut microbiome were explored to identify the potential biomarkers for this regimen. Twenty patients were consecutively enrolled and received study therapy. The trail met its primary endpoint with a median OS of 12.3 months (95% CI: 10.1‐14.5). Only four (20%) patients were observed of the grade 3 treatment‐related adverse events (TRAEs) and no grade 4 or 5 TRAEs were detected. Mutation of AGO2 was correlated with a significantly longer OS. Abundance of Proteobacteria was associated with inferior clinical response. Therefore, sintilimab plus anlotinib demonstrated encouraging anti‐tumor activity with a tolerable safety profile and deserved to be investigated in larger randomized trials for patients with advanced BTC subsequently. [ABSTRACT FROM AUTHOR]

Cholestasis is a main clinical feature of biliary atresia (BA), which leads to liver fibrosis (LF). The focus of BA treatment is preventing and slowing the progress of LF. This study reports the improvement effect of anlotinib on common bile duct ligature (BDL)‐induced LF in young rats. The BDL young rats were treated with anlotinib and the serum levels of aspartate aminotransferase, alanine aminotransferase, albumin, and total bilirubin were determined. Histological staining was performed and pathological changes in liver tissue were observed. The expression levels of α‐SMA, collagen I, CD31, TGF‐β1, phospho‐VEGFR2, phospho‐4E/BP1, and phospho‐S6K1 were determined. The results showed that anlotinib significantly improved the liver function and histopathological injury of BDL rats, inhibited the deposition of collagen and hepatocyte apoptosis, and downregulated the protein expression of α‐SMA and collagen I. Furthermore, anlotinib treatment significantly inhibited microvascular formation in the liver and downregulated the expression level of phospho‐VEGFR2, thereby suggesting that the antifibrosis effect of anlotinib may be achieved by antiangiogenesis. In addition, anlotinib downregulated the expression of phospho‐S6K1 and upregulated the expression of phospho‐4E/BP1, two downstream proteins of the mammalian target of rapamycin (mTOR) pathway. MHY1485, an agonist of mTOR, significantly reversed the inhibitory effect of anlotinib on angiogenesis and LF but did not influence the effect of anlotinib on the downregulation of phospho‐VEGFR2 expression. Together, the above‐mentioned results suggest that the effect of anlotinib on BDL‐induced LF involves at least antiangiogenesis regulated by the VEGFR2/mTOR signaling pathway. [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]

Small cell lung cancer (SCLC) is an aggressive malignancy associated with poor prognosis. Metastasis to sites outside the chest at the time of initial diagnosis, such as bone, brain, and liver metastasis have been found in most SCLC patients. Iris metastases from SCLC have rarely been previously reported, and often cause eye pain and blindness in patients. Here, we report a patient with SCLC who presented with iris metastasis in the right eye and metastasis in the left adrenal gland due to disease progression on first-line therapy, which subsequently caused pain and blindness in the right eye. The patient was treated with second-line irinotecan combined with anlotinib and atezolizumab and did not receive any local treatment in the right eye. After only one cycle of treatment, the iris metastases in the right eye were smaller than before, and the visual acuity in the right eye recovered. At the same time, her left adrenal metastases were also significantly smaller than before. Our case suggests that systemic therapy with effective treatment options can similarly improve iris metastases in patients. [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: 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]

Anlotinib is a novel small molecule multitarget tyrosine kinase inhibitor for the treatment of several cancers. We developed and validated a highly sensitive, rapid and stable high‐performance liquid chromatography–mass spectrometrymethod for the determination of anlotinib in human plasma with anlotinib‐d5 as a stable isotopically labeled internal standard (SIL‐IS). To explore the feasibility of therapeutic drug monitoring in the treatment of tumors with anlotinib, human plasma samples were prepared by protein precipitation. The mobile phases comprised of (A) 5.0 mm NH4AC aqueous solution containing 0.1% formic acid and (B) 100% methanol containing 0.1% formic acid. A gradient mobile phase system was adopted for chromatographic separation using a BEH C18 (2.1 × 50 mm, 1.7 μm) column. A positive ion pattern was chosen for quantification under multiple reaction monitoring mode. The ion pairs were detected at m/z 408.2 → 339.1 and m/z 413.4 → 344.3 for anlotinib and anlotinib‐d5 (SIL‐IS), respectively. The total run time was 5.0 min. The calibration curve was found to be linear within a plasma concentration range of 2–400 ng·ml−1. The precision and accuracy, matrix effect, extraction recovery and stability were all validated and met the requirements of international guidelines. The proposed methods were successfully applied to support therapeutic drug monitoring in breast and thyroid cancer patients receiving anlotinib for therapy. Clinical data showed that in the 12 mg dose group, the mean plasma concentrations of anlotinib in breast cancer patients and thyroid cancer patients were 87.1 and 118.8 ng·ml−1, respectively. The data demonstrate that the peak concentration of anlotinib may be related to the different tumor types in patients. [ABSTRACT FROM AUTHOR]

Background: Anlotinib as a third‐line or beyond therapy for extensive‐stage small‐cell lung cancer (ES‐SCLC) was studied. This single‐arm phase II trial was to investigate the value of anlotinib plus platinum‐etoposide as first‐line treatment in ES SCLC. Methods: The primary endpoint was progression‐free survival (PFS) and objective response rate (ORR). The secondary endpoints included overall survival (OS), disease control rate (DCR), time to progression (TTP), duration of remission (DoR), and safety. The subgroups of preset liver metastasis and brain metastasis were analyzed. Results: In 35 ES‐SCLC patients, the median PFS, ORR, DCR, and OS were 8.02 months [95% confidence interval (CI): 6.90–9.66], 85.71% (95% CI: 69.74–95.19), 94.29% (95% CI: 80.84–99.30), and 15.87 months (95% CI: 10.38–18.89), respectively. The median PFS in the liver metastasis and brain metastasis subgroups was 7.33 months (95% CI: 4.76–9.69) and 7.34 months (95% CI: 5.68–9.20), respectively. The most common AEs with grade 3–4 were hand–foot syndrome (17%), granulocytosis (17%), stomatitis (14%), hypertriglyceridemia (11%), hypercholesterolemia (11%), as well as nausea and vomiting (11%), and no grade 5 AEs were recorded. Conclusions: Anlotinib combined with platinum‐etoposide provided an effective and safe therapy for patients with ES‐SCLC. [ABSTRACT FROM AUTHOR]

Background: The aim of this prospective, pilot, single‐arm phase II trial was to evaluate the safety and efficacy of anlotinib combined with etoposide and platinum‐based regimens in the first‐line treatment of extensive‐stage small cell lung cancer (ES‐SCLC). Methods: This phase II study was conducted at Fudan University Shanghai Cancer Center between December 2018 and December 2020. All patients received standard chemotherapy (etoposide plus cisplatin/carboplatin) consisting of four courses and anlotinib at 12 mg once per day for 2 weeks followed by a one‐week rest. Anlotinib administration was continued until disease progression, intolerable adverse events (AEs) or patient withdrawal from the study. The primary outcome measure was progression‐free survival (PFS). The secondary outcome measures were overall survival (OS), objective control rate (ORR), disease control rate (DCR) and AEs. Results: Thirty‐seven patients were included in this study, and 30 patients were eligible for efficacy analysis. ORR and DCR were 90.0% and 96.7%, respectively. The estimated PFS and OS were 6.0 months (95% CI: 1.1–11.9 months) and 14.0 months (95% CI: 8.6–19.4 months), respectively. No unexpected adverse effects were reported. Hypertension (20/37, 54.1%), anemia (16/37, 43.2%), alopecia (15/37, 40.5%), elevated transaminases (9/37, 24.3%) and alkaline phosphatase (9/37, 24.3%) were the most commonly reported AEs. Thirteen patients (35.1%) reported grade 3–5 AEs. No treatment‐related deaths occurred during this study. Conclusion: The addition of anlotinib to standard etoposide/platinum chemotherapy achieved encouraging PFS and OS in previously untreated ES‐SCLC patients, with an acceptable tolerability profile and no new safety signals observed. [ABSTRACT FROM AUTHOR]

Anlotinib is a small molecule of novel tyrosine kinase inhibitor initially approved to treat non‐small cell lung cancer in China. Drug–drug interaction (DDI) is an extrinsic factor important for the appropriate use of anlotinib in clinical practice. In vitro experiments demonstrated that anlotinib is a substrate of cytochrome P450 (CYP) enzymes and moderate inhibitor of several common ones; however, no clinical DDI studies have been performed to investigate inhibitory effects of anlotinib on these CYP enzymes. Thus, its drug label recommends avoiding co‐administration with substrates of these enzymes, which have narrow therapeutic windows. In this study, we performed a CYP450 inhibition study, followed by gathering in vitro and clinical pharmacokinetic data to build the first physiologically based pharmacokinetic (PBPK) model of anlotinib. The verified model was subsequently used to predict the DDI mediated by anlotinib. As a result, the marginal plasma exposure changes of typical CYP3A and CYP2C9 substrates were less than the bioequivalence threshold, indicating that anlotinib has a very low potential of causing clinically meaningful DDI through the inhibition of several major CYP enzymes. According to the FDA's latest guideline on DDI, the established model with the simulation results may support the revision of anlotinib labelling without further clinical studies, lifting unnecessary restrictions on anlotinib regimens. [ABSTRACT FROM AUTHOR]

Adenosine deaminases acting on RNA 1 (ADAR1) has been identified to play key roles in non‐small cell lung cancer (NSCLC) progression, and can modulate the sensitivity of cancer cells to anticancer drugs. The current study aimed to investigate the effect of ADAR1 on the sensitivity of NSCLC cells to anlotinib. We established anlotinib‐resistant NSCLC (NSCLC/AR) cells, including NCI‐H1975/AR and A549/AR cells. Results showed that ADAR1 was significantly upregulated in NSCLC/AR cells. Genetic‐knockdown of ADAR1 increased the sensitivity of NSCLC/AR cells to anlotinib by inducing cell proliferation suppression, cell cycle arrest, and apoptosis. Furthermore, knockdown of ADAR1 decreased the level of C‐X3‐C motif chemokine ligand 1 (CX3CL1) in NCI‐H1975/AR and A549/AR cells after anlotinib treatment. Introduction of exogenous CX3CL1 significantly reversed the positive effect of ADAR1 deficiency on NSCLC/AR cell sensitivity, exhibited by the increase of cell viability and decrease of apoptosis. Further in‐vivo study demonstrated that knockdown of ADAR1 inhibited NCI‐H1975/AR cell tumorigenesis by reducing CX3CL1 expression. Collectively, ADAR1 deficiency increased the sensitivity of NSCLC/AR cells to anlotinib by downregulating CX3CL1, which might provide a potential strategy for NSCLC/AR therapy. [ABSTRACT FROM AUTHOR]

Liver metastasis is common in advanced small cell lung cancer (SCLC). There is no evidence-proven treatment beyond the second line in patients with SCLC and liver metastasis. This study aimed to investigate survival in patients with SCLC and liver metastasis treated with anlotinib compared with placebo. This study was a post hoc analysis of the phase II ALTER 1202 trial, including patients who had liver metastasis at baseline. The participants were randomized 2:1 to receive either 12 mg/day anlotinib (anlotinib group) or placebo (placebo group). Tumor response, progression-free survival (PFS), and overall survival (OS) were compared. In the original trial, there were 39 participants with liver metastasis at baseline, including 27 and 12 in the anlotinib and placebo groups, respectively. The objective response rate was 3.7% and 0% in the anlotinib and placebo groups, respectively (p = 0.9999). An elevated disease control rate was found in the anlotinib group (44.4%) compared with the placebo group (8.3%, p = 0.0173). The median PFS was 1.51 vs. 0.71 months in favor of anlotinib (hazard ratio [HR] = 0.365, 95% confidence interval [CI]: 0.17-0.78; p = 0.0064), with no marked difference in median OS (3.29 vs. 1.91 months; HR = 0.51, 95% CI: 0.22-1.16; p = 0.0996). The most common AEs in the anlotinib group were hypertension (40.7%), fatigue (29.6%), loss of appetite (22.2%), and weight loss (22.2%). There were no grade 5 AE. In conclusion, anlotinib increased PFS compared with placebo in patients with SCLC and liver metastasis. [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]

Background: Tyrosine kinase inhibitors (TKIs) such as cabozantinib, regorafenib have demonstrated encouraging activity in prolonging progression‐free survival (PFS) in several bone sarcoma entities in prospective clinical trials. This retrospective study aims to analyze the safety and efficacy of anlotinib, a novel multi‐target TKI, in patients with locally unresectable or metastatic bone sarcoma at three institutions. Methods: Patients with advanced bone sarcoma administered anlotinib 12 mg once daily, 2 weeks on/1 week off, from June 2018 to June 2020, until disease progression or intolerance of treatment. The primary endpoints were objective response rate (ORR) and PFS. Results: Forty‐eight patients were analyzed: 27 have osteosarcoma, 9 have chondrosarcoma, 8 have Ewing's sarcoma, and 3 have chordoma. The median age was 24 years (range, 16–68 years), and the median number of prior regimens was 1 (range, 0–4). Until the final follow‐up, five patients obtained a partial response and while 24 achieved stable disease. The ORR in all patients was 10.4%, and the median PFS was 4.6 months, with a progression‐free rate (PFR) at 3 months and 6 months of 72.9% and 35.4%, respectively. The ORR and median PFS varied much among tumor subtypes. The most frequent grade 3–4 adverse events (AEs) were pneumothorax, hand‐foot syndrome, cholesterol elevation, hypertriglyceridemia, and fatigue. No patients died from anlotinib‐related AEs during the study period. Conclusions: Anlotinib may show promising antitumor activity in unresectable or metastatic bone sarcoma. The ORR and median PFS of anlotnib are similar to those of other targeted drugs in different subtypes of sarcomas. The AEs were generally mild and tolerated well. Further studies of anlotinib in selected subtypes of bone sarcoma are needed. [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]

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]

Anlotinib is a multi‐target tyrosine kinase inhibitor. Previous studies confirmed that anlotinib exerts anti‐cancer efficiency. However, the functional roles of anlotinib on cancer stem cells (CSCs) are yet to be elucidated. In this study, lung CSCs were isolated and identified in vitro, and mouse xenografts were established in vivo. MTT assays, tumour sphere formation assays, TdT‐mediated dUTP nick‐end labelling (TUNEL) staining, Annexin V‐FITC/PI staining, immunofluorescence analysis and Western blot were performed to investigate the anti‐cancer effects of anlotinib on lung CSCs. The results showed that anlotinib inhibits the growth of lung CSCs in vitro and in vivo. In addition, anlotinib induced apoptosis of these cells along with down‐regulated expression level of Bcl‐2 whereas up‐regulated Bax and cleaved caspase‐3 expression. It also sensitized lung CSCs to the cytotoxicity of cisplatin and paclitaxel; the tumour sphere formation and expression levels of multiple stemness‐associated markers, such as ALDH1 and CD133, were also decreased. Furthermore, the underlying mechanism indicated that anlotinib reduces the phosphorylated levels of NF‐κB p65 and IκB‐α in lung CSCs. Taken together, these findings suggested that anlotinib exerts potent anti‐cancer effects against lung CSCs through apoptotic induction and stemness phenotypic attenuation. The mechanism could be associated with the suppression of NF‐κB activity. [ABSTRACT FROM AUTHOR]

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 < 0.001). The apoptotic cell statistics of H520 cells in the control group, A group, RT group and A + RT group were significantly different (F = 44.537, P < 0.01). The relative expression of CDK1 in each group of cells was 0.04 ± 0.02, 0.07 ± 0.12, 0.81 ± 0.11, and 0.56 ± 0.16, respectively. There were differences between the groups by analysis of variance which were statistically significant (F = 58.36, P < 0.0001). The relative expression of cycle B in each group of cells was 0.27 ± 0.05, 0.40 ± 0.16, 0.65 ± 0.14, and 0.57 ± 0.13, respectively. There were differences between the groups by analysis of variance which were statistically significant (F = 10.77, P = 0.0002). Conclusions: Anlotinib had an inhibitory effect on lung cancer H520 cell proliferation. A higher rate of apoptosis and G2/M phase block was observed in the anlotinib‐radiotherapy combined group. Anlotinib combined with radiotherapy was able to synergistically inhibit tumor cell growth. Key points: Anrotinib combined with radiotherapy can synergistically inhibit tumor cell growth. [ABSTRACT FROM AUTHOR]

Background: Currently, there are no randomized trials on the effect of antiangiogenic therapy in patients with esophageal squamous cell carcinoma (ESCC). The following study investigated the efficacy and safety of anlotinib in patients with advanced ESCC who were previously treated with chemotherapy. Methods: This randomized, placebo‐controlled, double‐blind phase 2 trial (NCT02649361) was conducted in 13 Chinese hospitals. Eligible patients were adults with histologically confirmed recurrent or metastatic ESCC who were previously treated with chemotherapy, and were randomly assigned (2:1) to receive oral anlotinib 12 mg or placebo on days 1–14 (repeated every 21 days). The primary endpoint was progression‐free survival (PFS). Results: One hundred and sixty‐five patients were randomly assigned to the anlotinib (n = 110) or the placebo (n = 55) arm. Median PFS was 3.02 months (95% CI 2.63–3.65) in the anlotinib group and 1.41 months (95% CI 1.38–1.41) in the placebo group (hazard ratio 0.46 [95% CI 0.32–0.66]; p < 0.001). The most common treatment‐related adverse events of grade 3 or 4 were hypertension (17 [16%] patients), decreased appetite (6 [6%] patients), and hyponatremia (4 [4%] patients) in the anlotinib group and decreased appetite (2 [4%] patients) in the placebo group. Three (3%) deaths in the anlotinib group were considered as drug related, while there were no treatment‐related deaths in the placebo group. Conclusions: The use of anlotinib in previously treated, recurrent, or metastatic ESCC patients significantly improved PFS compared with placebo. Our findings suggest that antiangiogenesis might be an important therapeutic target in advanced ESCC. Clinical Trials Registration: Study of Anlotinib in Patients With Esophageal Squamous Cell Carcinoma (ALTER1102), NCT02649361. [ABSTRACT FROM AUTHOR]

The purpose of this prospective phase II clinical trial was to investigate the efficacy and safety of anlotinib in patients with relapsed small cell lung cancer (SCLC). Forty‐five patients with relapsed SCLC were enrolled and treated with anlotinib (one cycle of 12 mg daily for 14 days, discontinued for 7 days, and repeated every 21 days) until disease progression or intolerance of treatment. The primary end point was progression‐free survival (PFS). Secondary end points were overall survival (OS), disease control rate (DCR), objective control rate (ORR) and toxicity. The median PFS was 4.1 months (95% confidence interval [CI] 2.4‐5.8) and the median OS was 6.1 months (95% CI 2.2‐10.0). The OS for the limited‐stage subgroup was significantly longer than that of the extensive‐stage subgroup (P =.02). The DCR was 67%, and the ORR was 11%. The most common adverse event was hypertension (13%), which was controlled well with antihypertensive drugs. In conclusion, anlotinib has likely efficacy in patients with relapsed SCLC, and the side effects can be well tolerated. A longer OS was observed in limited‐stage SCLC patients treated with anlotinib. What's new? Although untreated small cell lung cancer (SCLC) patients are usually sensitive to chemotherapy, they are prone to relapse. Anlotinib is a novel multi‐target small molecule tyrosine kinase inhibitor with both anti‐angiogenesis and anti‐tumor growth effects. While anlotinib became the first drug approved for third‐line and further‐line treatment of SCLC in China, few studies have focused on anlotinib treatment in relapsed SCLC. This one‐arm, prospective phase II clinical study reports a median progression‐free survival of 4.1 months (95% CI 2.4‐5.8) and median overall survival of 6.1 months (95% CI 2.2‐10.0) for anlotinib treatment in relapsed SCLC, with relatively mild side effects. [ABSTRACT FROM AUTHOR]

Thymic carcinoma is a rare and highly aggressive mediastinal tumor. Most patients are diagnosed at surgically unresectable stages. Current prospective and retrospective studies have indicated that platinum and anthracycline‐based chemotherapy are the first choice drugs of first‐line therapy for advanced thymic carcinoma. However, there is no optimal treatment after progression for patients who have undergone first‐line and subsequent chemotherapy. Anlotinib, a novel small molecule tyrosine kinase multitarget inhibitor, was approved by the China Food and Drug Administration as a third‐line treatment for advanced non‐small cell lung cancer (NSCLC) in May 2018. Herein we report a case of an advanced thymic squamous cell carcinoma patient harboring EGFR exon 20 insertion who had previously received multiline therapy, including chemotherapy, radiotherapy as well as antiangiogenic therapy. Also as an angiogenesis inhibitor, anotinib had controlled his mediastinal mass after failure of the apatinib treatment. To date, over 23 months of progression‐free survival (PFS) and six years of overall survival (OS) have been achieved. Compared with apatinib, the adverse reactions have been mild and tolerable and the patient's quality of life has improved. To our knowledge, this is the first report where anlotinib has been effective in controlling the progression of thymic carcinoma. In the multiline treatment of advanced thymic carcinoma, anlotinib appears to show great potential when utilized as a salvage treatment. [ABSTRACT FROM AUTHOR]

Background: Although many studies have defined mechanisms of resistance to EGFR‐TKIs, acquired resistance remains the major limitation of monotherapy with EGFR‐TKIs. Methods: Cell viability was analyzed using a Cell Counting Kit‐8 (CCK‐8) assay. EGFR T790M mutation was sequenced on a HiSeq 4000 platform. mRNAs from HCC827 and HCC827 gefitinib‐resistant (GR) cells were analyzed by genome analyzer‐based deep sequencing. The effect of anlotinib on apoptosis and cell cycle arrest of HCC827 GR was detected by fluorescence‐activated cell sorting (FACS) analysis. A mouse xenograft model was used to assess the effect of anlotinib on HCC827 GR cells. Results: The T790M mutation was found in the PC‐9 GR cell line but not in the HCC827 GR cell line. Anlotinib could suppress the growth of HCC827 GR cells by inhibiting FGFR1 in vitro and in a mouse xenograft model. Moreover, FGFR1 was overexpressed in HCC827 GR cells, and the knockdown of FGFR1 reversed gefitinib resistance in HCC827 GR cells. Furthermore, anlotinib induced apoptosis and cell cycle arrest in HCC827 GR cells by increasing the activity of Caspase‐3. Conclusions: FGFR1 overexpression could be the mechanism of EGFR‐TKI acquired resistance and anlotinib can suppresse the growth of EGFR‐TKI‐resistant NSCLC cells without T790M mutation. [ABSTRACT FROM AUTHOR]

Background: Anlotinib is a novel, orally administered, multitarget receptor tyrosine kinase inhibitor. It functions by inhibiting tumor angiogenesis and proliferative signaling pathways. In this study, we aimed to investigate the efficacy and safety of anlotinib plus epirubicin in a sarcoma patient‐derived xenografts (PDX) model. Methods: We firstly established a PDX model using fresh tumor tissues that were surgically removed from a patient diagnosed with malignant fibrous histiocytoma. Thirty‐six PDX models were divided into six groups and treated with anlotinib alone (low‐dose, 1.5 or high‐dose, 3.0 mg/kg/day, oral gavage), or with anlotinib plus epirubicin (3.0 mg/kg/once weekly, i.p.) when the tumors grew to 150‐200 mm3. After 5 weeks of treatment, the mice were sacrificed, and the tumors were measured by weight and processed for IHC and H&E staining. IHC staining was performed to detect CD31, EGFR, MVD, and Ki‐67 on paraffin sections. H&E stainings were performed to examine the microcosmic changes that occurred in the tumor tissues and myocardium, respectively. Results: After 5 weeks, treatment with anlotinib or epirubicin alone significantly inhibited tumor growth in the sarcoma PDX model compared with the vehicle control. Tumor volume in the high‐dose anlotinib group was significantly smaller than the low‐dose anlotinib group (P <.001). Combined high‐dose anlotinib and epirubicin treatment resulted in the most pronounced tumor inhibition. In the groups treated with the anlotinib‐containing regimen, the expression levels of CD31, EGFR, MVD, and Ki‐67 were significantly low. The weight in each group had no statistical differences; the same applied to the hepatic function, cardiac function, and toxicity. Conclusions: High‐dose anlotinib combined with epirubicin was an effective and safe therapy for STS. [ABSTRACT FROM AUTHOR]

Introduction: About 50% of patients with non‐small cell lung cancers (NSCLC) are diagnosed with brain metastases during treatment, and stereotactic radiosurgery (SRS) is an important treatment for brain oligometastasis. Some patients with brain metastases have cerebral edema before treatment, and radiation therapy may also cause, or aggravate brain edema. Vascular endothelial growth factor (VEGF) promotes angiogenesis and increase vascular permeability, and previous studies have shown that anti‐VEGF treatment can reduce brain edema. We hypothesized that anlotinib hydrochloride can reduce perilesional edema around brain metastases, create conditions for subsequent SRS, increase local control rate and improve patient prognosis. Methods: From one week before stereotactic radiosurgery, patients begin to receive anlotinib once a day (12 mg) from day 1–14 of a 21 day cycle, with two cycles in total. Brain magnetic resonance imaging (MRI) scan is taken before treatment, one week and one month after medication. A total of 50 patients will be included in this study. The primary endpoint is the Edema Index, and the secondary endpoints are intracranial objective response rate (iORR), intracranial progression‐free survival (iPFS), objective response rate (ORR), disease control rate (DCR), progression‐free survival (PFS), overall survival (OS), safety, and the rate of SRS after anlotinib treatment. Discussion: This study is a multicenter, prospective, single‐arm, phase II clinical study, and explores the efficacy and tolerability of SRS with anlotinib in NSCLC patients with limited brain metastases. The aim of the study is to provide new treatment options for NSCLC patients with brain metastases. [ABSTRACT FROM AUTHOR]

Background: Anlotinib showed significant survival benefits in advanced non‐small cell lung cancer (NSCLC) patients as a third‐ or further‐line treatment in the ALTER0303 trial. We aimed to evaluate the efficacy of anlotinib in patients with different histologies. Methods: The ALTER0303 trial was a randomized, open‐label, phase 3 study of anlotinib in NSCLC patients previously treated with at least two lines of chemotherapy or a tyrosine kinase inhibitor (TKI) in 31 centers in China. Patients were randomly assigned at a 2:1 ratio to receive anlotinib (12 mg QD from days 1 to 14 of a 21‐day cycle) or placebo until progression or intolerable toxicity. The primary endpoint was overall survival (OS). We assessed the efficacy of anlotinib in histological subgroups in the full analysis set. Results: In the ALTER0303 trial, 336 patients had the histological subtype of adenocarcinoma (ACC), 86 patients had the histological subtype of squamous cell carcinoma (SCC), and 15 patients had another subtype. In the ACC subgroup, the median OS time was significantly improved with anlotinib compared with placebo (9.6 months vs 6.9 months, P =.0051), as was the median progression‐free survival (PFS) time (5.5 months vs 1.4 months, P <.0001). In the SCC subgroup, the median OS time was 10.7 months in the anlotinib group and 6.5 months in the placebo group (P =.2570), and the median PFS time was 4.8 months and 2.7 months (P =.0004), respectively. The common adverse events observed in the SCC and ACC subgroups were similar. Conclusions: Our findings suggest that anlotinib significantly improves PFS and OS in ACC patients and has a tendency to prolong survival in SCC patients. [ABSTRACT FROM AUTHOR]

Superior to chemotherapy, photonic hyperthermia and targeted therapy have made attractive impacts on cancer treatment by virtue of their profound advantages such as high specificity and minimal invasiveness, but the rational integration of corresponding therapeutic drugs for achieving concurrent photothermal ablation/targeted therapy is still challenging. Herein, a self‐assembled nanomedicine Anlotinib@IR820 is constructed with drug formulations for highly efficient and synergistic photonic hyperthermia and targeted therapy against breast cancer. Specifically, the constructed Anlotinib@IR820 nanomedicine presents high accumulation at the tumor site owing to the enhanced permeability and retention effect and simultaneously overcomes the obstacles of poor water solubility of Anlotinib (for targeted therapy) and the short lifetime of IR820 (for photonic ablation). The photothermal ablation as activated by near‐infrared laser can not only irradiate cancer cells but also promote the cellular uptake of Anlotinib, which presents a profound synergistic function both in vitro and in vivo. Mechanically, Anlotinib@IR820 nanomedicine can induce apoptosis and cause cell cycle arrest in breast cancer through inhibiting ERK, AKT, and STAT3 pathways. Therefore, the rationally designed drug‐composed Anlotinib@IR820 nanomedicine exhibits high clinical translation potential because of its therapeutic nanoformulation, which provides an alternative option for efficient combinational therapy of breast cancer. [ABSTRACT FROM AUTHOR]

Anlotinib is an anti‐angiogenic drug that targets vascular endothelial growth factor receptor, platelet‐derived growth factor receptor, fibroblast growth factor receptor, c‐Kit, and other kinases and has been approved for the treatment of advanced non‐small cell lung cancer (NSCLC). As in other small‐molecule tyrosine kinase inhibitors, adverse effects such as hypertension and cardiotoxicity may be seen. However, the relationship between anlotinib and aortic dissection has not been previously reported. Here, we present a case of aortic dissection in a 58‐year‐old male patient with advanced NSCLC without history of hypertension who received anlotinib as third‐line treatment. After four courses of anlotinib treatment, he suffered a sudden onset of back pain, sweating, anxiety, and high blood pressure (180/120 mmHg) and heart rate (137 bpm). Emergency computed tomographic angiography revealed aortic dissection and thrombosis of the distal false lumen. Thereafter, the patient was administered nitroglycerin as antihypertensive treatment and he underwent stent‐graft intervention for aortic dissection. Anticoagulants and antihypertensive drugs were administered after the operation, and a moderate control of blood pressure was achieved. Thus, the adverse reactions of antolinib must be monitored and clinicians must be vigilant. [ABSTRACT FROM AUTHOR]

Radiation pneumonitis is a serious side effect of thoracic radiotherapy with no established treatment currently. Anlotinib is a small‐molecule tyrosine kinase inhibitor (TKI) with anti‐angiogenic effects. The effect of TKIs in the treatment of radiation pneumonitis remains to be elucidated. We investigated whether anlotinib could alleviate radiation pneumonitis. We report a case of a patient with esophageal cancer who received anlotinib for radiation pneumonitis following radiotherapy. We also reviewed related studies to address this issue. The results in this patient suggest that anlotinib may be a valid treatment option for radiation pneumonitis. [ABSTRACT FROM AUTHOR]

Patients with tongue squamous cell carcinoma (TSCC) and cervical lymph node metastasis are particularly difficult to treat. This is the first report of about anlotinib combined with docetaxel chemotherapy for chemotherapy‐refractory TSCC with cervical lymph node metastasis, may provide a new, suitable therapeutic option for these patients. [ABSTRACT FROM AUTHOR]