Early Structural, Biochemical, and Metabolic Responses to Anlotinib in Patients With Progressive Radioactive Iodine Refractory Differentiated Thyroid Cancer.

OBJECTIVE: We aimed to assess the early efficacy of anlotinib in patients with progressive radioactive iodine refractory differentiated thyroid cancer at the structural, biochemical, and metabolic levels. METHODS: Ten eligible patients were prospectively enrolled to receive anlotinib. Their responses were assessed at 6 weeks. Apart from the structural response according to Response Evaluation Criteria in Solid Tumors version 1.1, the biochemical response was assessed by serum thyroglobulin (Tg), and the metabolic response was assessed by 2-deoxy-2-[18F] fluoro-D-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) according to the European Organization for Research and Treatment of Cancer criteria. A safety profile was recorded. RESULTS: Structurally controlled disease (20% partial response + 80% stable disease) was observed in all patients. The median longest diameter of target lesions shrank from 20.8 mm (IQR, 14.9-27.5) to 17.0 mm (IQR, 14.1-23.7) (P < .001), and the average shrinkage rate was -15.1 ± 14.1%. Sharp serum Tg reduction by 72.8 ± 16.4% was observed in 8 measurable patients. The 18F-FDG PET/CT-mapped glucose metabolic response was not quite comparable to the structural response, with 90% of the patients having controlled disease (30% partial metabolic response + 60% stable metabolic disease), whereas 10% presented progressive metabolic disease. The most common treatment-emergent adverse events (AEs) were hypertension (100%) and proteinuria (70%). Most AEs were grade 1 or 2, whereas grade 3 AEs occurred only in hypertension. CONCLUSION: Anlotinib is generally well tolerated and can bring early disease control within the initial 6 weeks of treatment. The sharp biochemical response suggests Tg to be an early sensitive biomarker to anlotinib, whereas the heterogeneous metabolic response might play a complementary role.

Efficacy and safety of XELOX combined with anlotinib and penpulimab vs XELOX as an adjuvant therapy for ctDNA-positive gastric and gastroesophageal junction adenocarcinoma: a protocol for a randomized, controlled, multicenter phase II clinical trial (EXPLORING study).

Background: The efficacy of current adjuvant chemotherapy for gastric adenocarcinoma/gastroesophageal junction adenocarcinoma (GA/GEJA) leaves much to be desired. ctDNA could serve as a potential marker to identify patients who are at higher risk of recurrence. Reinforcing standard adjuvant chemotherapy with immunotherapy has already been indicated to significantly improve clinical outcome, albeit such evidence is rare in GA/GEJA. Here, we intend to explore the clinical benefit of the reinforcement of adjuvant immunotherapy and antiangiogenics alongside with chemotherapy in patients who are deemed in high risk of recurrence by ctDNA analysis, which might shed light on further improvements in adjuvant therapy for GA/GEJA. Methods/Design: This study is designed as a prospective, multicenter, randomized, controlled phase II study in patients histologically or cytologically diagnosed with GA/GEJA who underwent D2 gastrectomy and achieved R0 or R1 resection. From February 2022, a total of 300 stage III patients will be enrolled and subjected according to ctDNA sequencing results, and those with positive results will subsequently be randomized 1:1 to arm A or B. Patients in arm A will receive anlotinib, penpulimab and XELOX for 6-8 cycles, maintained with anlotinib and penpulimab for up to 1 year, while patients in arm B will receive XELOX alone for 6-8 cycles. ctDNA-negative patients will be assigned to arm C, and patients who are ctDNA positive but failed in randomization will be assigned to arm D. Patients in arms C and D will receive the investigator's choice of therapy. The primary endpoint is the median disease-free survival (DFS) of arm A versus arm B determined via CT/MRI imaging. Secondary endpoints include the DFS of ctDNA positive patients versus ctDNA negative patients, the 2- and 3-year DFS rates, overall survival (OS), the impact of hallmark molecules on the treatment response, adverse events (AEs), and the impact of nutrition status or exercise on recurrence. Discussion: We expect that ctDNA would be a strong prognostic factor and ctDNA-positive patients are at higher risk of relapse than ctDNA-negative patients. The addition of anlotinib and penpulimab to XELOX, may contribute to delaying relapse in ctDNA-positive patients. Trial registration: https://www.clinicaltrials.gov, identifier NCT05494060.

Maintenance anlotinib improves the survival prognosis of extensive-stage small cell lung cancer: a single-arm, prospective, phase II study.

The extent to which anlotinib provides survival benefits in the maintenance therapy of extensive-stage small cell lung cancer (ES-SCLC) remains unclear. Thus, this study aimed to assess the efficacy and safety of anlotinib monotherapy as maintenance therapy following induction chemotherapy in ES-SCLC patients. 27 ES-SCLC patients registered at the First Teaching Hospital of Tianjin University of Traditional Chinese Medicine were screened from February 2022 to October 2022, of which 3 were not eligible. Eligible patients in stable status after first-line chemotherapy would subsequently accept oral anlotinib (12 mg, p.o., qd. on d1-d14, every 21 days). The maintenance method was continued until disease progression or unmanageable toxicity occurred. The primary endpoint is median progression-free survival (mPFS). The second endpoints include median duration of response (mDOR), median overall survival (mOS) and safety. The mPFS and mDOR have been determined (mPFS: 252 days, 95% CI: 217.782-286.218 days; mDOR: 126 days, 95% CI: 98.899-153.101 days). The mOS was not reached; only 7 patients were reached while 20 patients survived. The primary treatment-related adverse events included hypertension (n=7, 25.9%), fatigue (n=5, 18.5%), poor appetite (n=5, 18.5%), and others. Notably, no patients required a dose reduction due to the severity of adverse events. Patients were generally able to tolerate treatment with anlotinib and exhibited a favorable prognosis. Anlotinib achieved prospective efficacy and manageable safety in the maintenance treatment of ES-SCLC.

Prediction Model of Treatment Effect of Anlotinib on Extensive-stage Small Cell Lung Cancer Based on Combination of Disease and Syndrome Information / 肿瘤防治研究

Objective To construct a nomogram prediction model for the treatment effect of anlotinib with the participation of traditional Chinese medicine syndrome elements on the patients with extensive-stage small cell lung cancer (ES-SCLC) who previously received multiple lines of chemotherapy. Methods The clinical data of 127 patients with ES-SCLC who received at least two cycles of anlotinib treatment were retrospectively studied. Kaplan-Meier method was used to analyze the relationship between each factor and the overall survival time. Cox regression analysis was applied to screen the independent influencing factors of the prognosis of patients with ES-SCLC. R language was employed to build a nomogram prediction model, C-index was used to evaluate the model, and calibration curve was adopted to verify the accuracy of the model. Results Age, PS score, brain metastases, qi deficiency syndrome, yin deficiency syndrome, and blood stasis syndrome were related risk factors for ES-SCLC treated with anlotinib. PS score, brain metastasis, and blood stasis syndrome were independent prognostic factors. On the basis of these three independent influencing factors, a nomogram model was established to predict the prognosis of patients with ES-SCLC treated with anlotinib. The predicted risk was close to the actual risk, showing a high degree of coincidence. Conclusion The nomogram model established with PS score, blood stasis syndrome elements, and brain metastasis as independent factors can predict the prognosis of patients with ES-SCLC receiving second- and third-line treatment of anlotinib.

Successful inguinal interstitial brachytherapy in metastatic cervical carcinoma: a case report.

Background: Treatment of metastatic cervical cancer is a tricky issue. Currently, the National Comprehensive Cancer Network (NCCN) guideline recommends chemotherapy combined with bevacizumab for recurrent or metastatic cervical cancer. Still, the recurrence rate is high and the survival rate is low after standard treatment. We urgently need to achieve a multimodal therapy approach for recurrent or metastatic cervical cancer. Case description: We report the case of a patient with stage IB2 cervical squamous carcinoma who developed multiple metastases within a short term after receiving first-line standard treatment, and she underwent interstitial brachytherapy after systemic therapy with an encouraging outcome. The patient developed suspected inguinal lymph node metastases after 9 months at the end of first-line therapy and multiple metastases in the inguinal lymph nodes, anterior abdominal wall, and right lung after 17 months. As the patient had residual inguinal lymph nodes after systemic therapy, she received 3D-printed template-guided interstitial brachytherapy to the inguinal lymph nodes and maintenance therapy. By Sep 2023, she had achieved a good treatment outcome with a progression-free survival (PFS) of 36 months. Conclusion: Based on our patient response, when multiple metastases develop in the short term in early-stage cervical squamous carcinoma after first-line therapy, we may consider implementing local therapy combined with systemic therapy.

Posterior reversible encephalopathy syndrome associated with use of anlotinib to treat squamous cell carcinoma of the cervix: case report and literature review.

Background: Posterior reversible encephalopathy syndrome (PRES), a neurological disorder with an unknown aetiology, is characterised by visual impairment, headache, vomiting, seizures, and transient alterations in consciousness. Case report: We present the case of a 49-year-old woman with advanced cervical carcinoma who received second-line therapy with oral anlotinib (12 mg, days 1-14, every 21 days) and injectable tislelizumab (200 mg, day 1, every 21 days). After 7 days of anlotinib administration, she began experiencing symptoms suggestive of PRES and was diagnosed on day 11. Interruption of anlotinib and supportive treatment led to recovery of her binocular vision. The Naranjo score (+5) graded the causality of this reaction as probable, suggesting the possibility that the event may have been an adverse reaction to anlotinib. Ethics: This case report was approved by the Ethics Committee of the First Affiliated Hospital of Guangzhou University of Traditional Chinese Medicine (Reference no. K-2023-068, 2023/06/09). Informed consent was obtained from the patient and her family.

Xihuang Pill enhances anticancer effect of anlotinib by regulating gut microbiota composition and tumor angiogenesis pathway.

Lung cancer poses a serious threat to human health. Although targeted therapies have led to breakthroughs in the treatment of lung cancer, drug resistance and side effects limit their clinical applications. Xihuang pill (XHW), a classical anti-cancer traditional Chinese medicine formula, has been clinically proven to be an effective complementary therapy in the treatment of various of cancers. However, the underlying mechanism for its use in combination with anti-cancer drugs remains unclear. Here, we explored the anti-lung cancer effect of XHW combined with anlotinib in mice bearing Lewis lung cancer (LLC). We used gut microbiota and transcriptomics to elucidate the regulatory properties of XHW in improving anti-lung cancer effect of anlotinib. The results showed that combination treatment of XHW with Anlotinib significantly inhibited tumor growth in LLC-bearing mice. We found that XHW played a key role in the regulation of gut microbiota using 16 s rRNA sequencing analysis. Specifically, XHW increased the proportion of the beneficial bacteria Bacteroides and g_norank_f_Muribaculaceae. Based on transcriptomic analysis of tumor tissues, differentially expressed genes in the combination therapy group were related to biological processes concerning angiogenesis, such as regulation of blood vessel diameter, regulation of tube diameter, and regulation of tube size. Our data suggest that XWH enhances the anticancer effect of anlotinib by regulating gut microbiota composition and tumor angiogenesis pathway. Combination therapy with anlotinib and XHW may be a novel therapeutic strategy for lung cancer patients.

Treatment of MGMT promoter unmethylated glioblastoma with PD-1 inhibitor combined with anti-angiogenesis and epidermal growth factor receptor tyrosine kinase inhibitor: a case report.

Glioblastoma (GBM) is the most common primary central nervous system (CNS) malignancy in adults and is associated with poor prognosis, especially even worse in those with unmethylated MGMT promoter. Currently, maximal safe resection combined with temozolomide (TMZ) concurrent chemoradiotherapy and TMZ adjuvant chemotherapy has been considered the standard treatment for newly diagnosed GBM. The efficacy of drugs other than TMZ is currently undefined. With increasing understanding of the biological characteristics of GBM, more and more studies are being conducted on drug targets, such as specific signaling pathways and microenvironment. Herein, we report the case of a GBM patient with unmethylated MGMT promoter who was intolerant to TMZ, and underwent treatment with the combination of carelizumab, anlotinib, and oxitinib during radiotherapy according to results of whole-exome sequencing (WES) and the patient's condition. The progression-free survival (PFS) and overall survival (OS) for this case were respectively nearly 11 and 18 months, significantly exceeding the historical data and the tolerance of the treatment for this case without sever adverse effects was favorable. Our case provides clinical evidence supporting the efficacy of the above three drugs and radiotherapy, which may translate into novel individualized treatment strategies for GBM patients who are intolerant to TMZ.

An Integrative Metabolomic and Network Pharmacology Study Revealing the Regulating Properties of Xihuang Pill That Improves Anlotinib Effects in Lung Cancer.

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.

Anlotinib followed by transarterial chemoembolization and radiofrequency ablation is a safe and effective initial treatment for hepatocellular carcinoma patients with portal vein tumor thrombus: A retrospective case series study.

BACKGROUND: Portal vein tumor thrombus (PVTT) remains a poor prognostic factor occurring in about 10%-40% of patients with hepatocellular carcinoma (HCC) for the optimal treatment is controversial. Anlotinib is an novel small molecule inhibitor that has a broad spectrum of inhibitory activities on tumor angiogenesis and growth. However, so far, no studies have reported the use of anlotinib in the treatment of HCC patients with PVTT. Here, we evaluated the safety and efficacy of anlotinib, followed by transarterial chemoembolization (TACE) and radiofrequency ablation (RFA) for the treatment of patients with HCC and PVTT. MATERIALS AND METHODS: A total of 145 consecutive HCC patients who underwent TACE in combination with RFA were enrolled in the retrospective study. Twenty-eight patients were diagnosed with PVTT and received anlotinib as basic treatment. The adverse events (AEs) were graded according to the National Cancer Institute Common Terminology Criteria for AEs Version 4.0. Time to tumor progression (TTP) and overall survival (OS) were calculated using the Kaplan-Meier method. RESULTS: The most common toxicities related to anlotinib were pharyngalgia (53.6%), fatigue (42.9%), and hand-foot skin reaction (39.3%). The median OS was 13 months (range: 3-18 months) with 1-year OS rate of 64.3%. The median TTP was 7 months (range: 1-12 months) with 6-month rate of 46.4%. CONCLUSION: Anlotinib followed by TACE and RFA is a safe and effective initial treatment modality for HCC patients with PVTT. Anlotinib may be a promising therapeutic option for relieving and/or stabilizing HCC with PVTT.

Traditional Chinese Medicine Brucea Javanica Oil Enhances the Efficacy of Anlotinib in a Mouse Model of Liver-Metastasis of Small-cell Lung Cancer.

BACKGROUND/AIM: Small-cell lung cancer (SCLC) is a recalcitrant disease with liver and other metastasis. The present study evaluated the efficacy of the traditional Chinese medicine Brucea javanica oil (BJO) combined with anlotinib, a multi-tyrosine kinase inhibitor with anti-angiogenic activity, on a nude-mouse model of SCLC liver metastasis. MATERIALS AND METHODS: The mouse model was established by injecting NCI-H446 cells (1×106) in Matrigel (20 µl) into the upper liver lobe. All animals were randomized and assigned to three groups: Control (n=8); anlotinib alone (n=8; 3 mg/kg, qd×14+7-day interval with two cycles, oral); anlotinib plus BJO (n=8; 3 mg/kg anlotinib qd×14+7-day interval with two cycles, orally; BJO: 1 g/kg, qd×6 weeks, orally). Body weight was determined every week. Six weeks after initial treatment, tumors were collected for analysis of angiogenesis using immunohistochemistry. RESULTS: The combination of anlotinib and BJO significantly inhibited growth of SCLC liver metastases and angiogenesis more than anlotinib monotherapy (p=0.043). In addition, BJO alleviated body-weight loss associated with anlotinib therapy, including general mouse condition. CONCLUSION: The results of the present study indicate that the combination of anlotinib with BJO is promisingly active against liver metastases of SCLC, and has clinical potential.

Clinical study of anlotinib combined with irinotecan in the third line treatment of metastatic esophageal cancer / 国际肿瘤学杂志

Objective:To investigate the clinical efficacy and adverse reactions of anlotinib combined with irinotecan in the third line treatment of metastatic esophageal cancer.Methods:From October 2018 to October 2019, 52 patients with metastatic esophageal cancer who had developed distant metastasis after receiving standard concurrent chemoradiotherapy and failed second-line chemotherapy were selected from Lu′an Hospital of Traditional Chinese Medicine of Anhui Province. The patients were divided into experimental group and control group by random number table method, with 26 cases in each group. The control group was given intravenous chemotherapy with irinotecan. The experimental group was treated with oral erlotinib combined with intravenous chemotherapy of irinotecan. The clinical efficacy and adverse reactions of the two groups were evaluated after 2 cycles of treatment.Results:Before treatment, there was no significant difference in Karnofsky performance status (KPS) score between the experimental group and the control group (76.15±7.52 vs. 74.62±8.59, t=-0.137, P=0.892). After treatment, there was no significant difference between the two groups (70.77±6.28 vs. 72.69±8.74, t=-1.761, P=0.084). However, after treatment, the KPS score in the experimental group was lower than that before treatment ( t=3.035, P=0.006). There was no statistical significance in the KPS scores of the control group before and after treatment ( t=1.000, P=0.327). Adverse reactions in the two groups were mainly grade 1-2. The incidences of grade 1-2 myelosuppression and diarrhea in the experimental group were 61.5% (16/26) and 46.2% (12/26), which were significantly higher than those in the control group (19.2%, 5/26 and 19.2%, 5/26), with statistically significant differences ( χ2=9.665, P=0.002; χ2=4.282, P=0.039). The disease control rate of the experimental group was 73.1% (19/26), which was significantly higher than that of the control group (46.2%, 12/26), and there was a statistically significant difference between the two groups ( χ2=3.914, P=0.048). The median progression-free survival of the experimental group and the control group was 52 days and 45 days, respectively, and there was a statistically significant difference ( χ2=4.692, P=0.032). Conclusion:Anlotinib combined with irinotecan in the third-line treatment of metastatic esophageal cancer has obvious efficacy, but to a certain extent, it increases the incidence of grade 1-2 myelosuppression and diarrhea, and the KPS score is lower compared with before treatment.