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Lung squamous cell carcinoma (LUSC) is the second most common pathological type of non-small cell lung cancer (NSCLC). However, compared with lung adenocarcinoma (LUAD), the incidence of driver gene mutations in LUSC is relatively lower and treatment options for LUSC patients are very limited. We described a LUSC patient with a novel FGFR3-IER5L fusion revealed by next generation sequencing in this report. The patient refused surgery, radiotherapy or chemotherapy and received anlotinib treatment. Anlotinib is a small molecular multi-target tyrosine kinase inhibitor, which can inhibit the activity of kinases including vascular endothelial growth factor receptor 2/3 (VEGFR2/3), fibroblast growth factor receptor 1-4 (FGFR1-4), platelet-derived growth factor receptor α/β (PDGFRα/β), and c-Kit. The patient achieved partial response and the progression-free survival was 3.8 months., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Chen, Zhao, Yu, Wang, Wang, Song, Meng and Li.)

Background: The anti-angiogenic agent anlotinib offers a new treatment option for triple-negative breast cancer (TNBC) patients with brain metastases. This study aimed to evaluate the efficacy and safety of anlotinib in the treatment of TNBC patients with brain metastases., Methods: Between October 2019 and April 2024, 29 TNBC patients with brain metastases who had failed prior therapy and were treated with anlotinib were retrospectively analyzed. The primary endpoint was central nervous system (CNS) progression-free survival (PFS), and secondary endpoints included overall survival (OS), intracranial disease control rate (iDCR), intracranial objective response rate (iORR), and safety., Results: The median CNS PFS of 29 patients was 7.2 months (95% confidence interval [CI], 3.5-10.9 months), and the median OS was 10.2 months (95% CI, 5.6-14.8 months). The iORR and iDCR were 31.0% and 86.2%, respectively. Five patients (17.2%) experienced grade 3-4 adverse events (AEs), with bone marrow suppression (2/29, 6.9%) being the most common. Most AEs were clinically manageable, and no treatment-related death was observed., Conclusion: Anlotinib demonstrated encouraging efficacy and manageable toxicity in the treatment of TNBC patients with brain metastases who had failed standard treatment., Competing Interests: The authors declare that the research was conducted without any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Liu, Li, Zhao, Liu and Sun.)

Pulmonary sarcomatoid carcinoma (PSC), a rare non-small cell lung cancer (NSCLC) subtype, poses diagnostic and treatment difficulties. Current research explores targeted therapies and immunotherapy to improve patient outcomes. This case report details a male patient diagnosed with PSC via pathology. Tests revealed high levels of PD-L1, a marker suggesting potential benefit from immune checkpoint inhibitors. However, despite bronchoscopic intervention, his advanced stage IIIB cancer (cT3N2bM0) progressed quickly, with progression-free survival (PFS) under 3 months. Following progression, the patient received tislelizumab (anti-PD-1 antibody) and anlotinib (an anti-angiogenic drug) as second-line therapy. This combination showed promise, achieving near-partial remission after the first cycle. Subsequent scans documented continued tumor shrinkage until the patient experienced fatal hemoptysis. This case highlights the potential benefits of combining tislelizumab with anlotinib for PSC. However, it also represents the first reported case of fatal hemoptysis with this specific treatment regimen. This finding emphasizes the need for increased awareness of this potential complication, especially in patients with centrally located PSC treated with anti-angiogenic agents like anlotinib., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Pu, Ma, Peng and Wang.)

Background: Sarcomatoid urothelial carcinoma (SUC) is a rare renal malignancy. Its biological malignancy is high, the prognosis is poor, diagnostic and treatment options are few, and there is no standard treatment plan., Case Presentation: In this case, a 64-year-old woman was hospitalized with fever and lower back pain one week previously. The preliminary diagnosis was a right kidney stone with a urinary tract infection. After the anti-infection treatment, a percutaneous right nephrostomy was performed. The intraoperative biopsy (renal pelvis) finding was infiltrating urothelial carcinoma with a sarcomatoid variation. Subsequently, radical surgery was performed for cancer of the right renal pelvis. Implant metastasis of the abdominal wall and adjacent abdominal cavity occurred half a month after the surgery. The lesion was resected again, and two cycles of doxorubicin plus carboplatin chemotherapy were administered. However, the disease progressed more rapidly after the chemotherapy. With the written consent of the patient, the treatment was altered to targeted immune therapy with toripalimab plus anlotinib. A clinical cure was achieved after nine cycles of treatment with no obvious lesions on imaging. The maintenance therapy was administered consecutively for over a year, and the patient is at present still in good condition with a disease-free survival exceeding two years., Conclusion: This case proves that the combination of toripalimab and anlotinib is effective in the treatment of recurrent renal SUC. To the best of our knowledge, this is the first reported case of a patient with advanced recurrent urothelial carcinoma of the renal pelvis sarcomatoid cured with this therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Hu, Deng, Pan, Zhang, Ruan, Jiang, Shen, Zhao and Dong.)

Background: Involvement of the distal fibula by alveolar soft-part sarcoma is rare. Extensive resection or amputation may be needed; however, distal fibula resection can disrupt foot and ankle biomechanics, leading to ankle joint instability. Reports on joint preservation for maintaining optimal ankle joint function are scarce. Computer-aided design and individualized three-dimensional (3D)-printed uncemented implants represent an evolving solution for reconstructing the distal fibula., Case Presentation: A 34-year-old woman was diagnosed with alveolar soft-part sarcoma in the right lower leg involving the cortical bone of the fibula. After anlotinib treatment, the tumor size decreased, and the tumor response rate was a partial response (PR); however, the patient continued to experience adverse reactions. With multiple disciplinary team discussions, surgical resection was deemed appropriate. Due to the extensive defect and ankle joint instability after resection, a custom-made 3D-printed prosthesis was designed and fabricated to reconstruct the defect, preserving the lateral malleolus. During the follow-up, the patient achieved favorable ankle function, and no prosthesis-related complications were observed., Conclusion: 3D-printed personalized uncemented implants constitute a novel approach and method for addressing the reconstruction issues of the distal fibula and ankle joint. Through the personalized design of 3D-printed prostheses, the lateral malleolus can be preserved, ensuring the normal anatomical structure of the ankle joint. They achieve a well-integrated interface between the prosthesis and bone, ensuring satisfactory postoperative function. Additionally, they offer valuable insights for reconstructing distal bone defects near joints in the extremities. However, confirming these findings requires extensive cohort studies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Xie, Gong, Wang, Li, Zhang, Lu, Luo, Min, Tu and Zhou.)

Background: Adrenocortical carcinoma (ACC) is a rare malignant tumor that occurs in the adrenal cortex. It has a high degree of malignancy and comparatively poor overall prognosis. Surgery is the standard curative therapy for localized ACC patients. The combination regimen of etoposide, doxorubicin, cisplatin (EDP) plus mitotane has been considered as the standardized chemotherapy regimen for advanced ACC. However, new effective regimens are emerging for specific conditions in metastatic ACC., Case Presentation: We report a case of a 66-year-old man diagnosed with metastatic ACC who had a large left adrenal mass (110 mm × 87 mm) and multiple metastases in both lungs. The patient was treated with EP and sintilimab for six cycles; anlotinib was introduced after the third cycle. Follow-ups after the second to fourth cycles found significantly reduced lung metastases with all imaging examinations indicating partial response (PR) status. The patient received maintenance therapy thereafter with sintilimab plus anlotinib. Until recently, the patient's lung metastases and the left adrenal gland area mass (39mm × 29mm) have disappeared, and no disease progression has been observed. The progression-free survival of this patient has been extended to approximately 31 months, in sharp contrast to a median survival time of 12 months for majority of advanced ACC. The main adverse events during treatment were appetite loss and grade I myelosuppression and revealed only grade I hypertension and grade I hypothyroidism., Conclusion: This case highlights the remarkable response of our patient's ACC to treatment with a novel combination of EP and sintilimab combined with anlotinib. Our findings suggest a safe and more effective combination therapeutic option for patients with adrenocortical carcinoma., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Niu, Zhang, Ma, Liang, Qiao, Wang and Niu.)

Objective: To systematically evaluate the efficacy and safety of anlotinib targeted therapy for the treatment of patients with advanced digestive system neoplasms (DSNs)., Methods: Clinical trials were extracted from PubMed, the Cochrane Library, Web of Science, Embase, China National Knowledge Infrastructure (CNKI) and the Wanfang database up to October 2023. Outcome measures, including therapeutic efficacy, quality of life (QOL) and adverse events, were extracted and evaluated., Results: Twenty trials, including 1,613 advanced DSNs patients, were included. The results indicated that, compared with conventional treatment alone, the combination of anlotinib targeted therapy with conventional treatment significantly improved the patients' 6-months overall survival (OS, OR=1.76, CI=1.53 to 2.02, P <0.00001), overall response (ORR, OR=1.76, CI=1.53 to 2.02, P <0.00001) and disease control rate (DCR, OR=1.51, 95% CI=1.25 to 1.84, P <0.0001). Moreover, the group that received the combined therapy had higher rates of hypertension ( P <0.00001), proteinuria ( P <0.00001), fatigue ( P <0.00001), diarrhea ( P <0.00001), hypertriglyceridemia ( P =0.02), alanine aminotransfease (ALT)increased ( P =0.004), aspartate transaminase (AST) increased ( P =0.006), anorexia ( P <0.00001), weight loss ( P =0.002), abdominal pain ( P =0.0006), hypothyroidism ( P =0.02), prolonged QT interval ( P =0.04). Analyses of other adverse events, such as gastrointestinal reaction, leukopenia, and neutropenia, did not reveal significant differences ( P >0.05)., Conclusion: The combination of anlotinib targeted therapy and conventional treatment is more effective for DSNs treatment than conventional treatment alone. However, this combined treatment could lead to greater rates of hypertension, albuminuria and hand-foot syndrome. Therefore, the benefits and risks should be considered before treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhou, Wang, Mu and Meng.)

Objective: The aim of this study was to investigate whether anlotinib could exert an inhibitory effect on the proliferation and invasion of cervical cancer cells by inhibiting cytokines secreted by activated cancer-associated fibroblasts (CAFs)., Methods: CAFs were isolated from cervical cancer tissues and experimentally studied in vivo and in vitro . Molecular biology experimental methods were used to verify whether anlotinib could inhibit the pro-carcinogenic effects of CAFs derived from cervical cancer tissues., Results: CAFs promote the proliferation and invasion of cervical cancer cells. Anlotinib inhibited the activation of CAFs and suppressed the promotion of cervical cancer cells by CAFs. Anlotinib inhibited the expression of multiple cytokines within CAFs and suppressed the release of interleukin (IL)-6 (IL-6) and IL-8. In vivo studies have shown that anlotinib diminished the growth of xenografted cervical cancer cells, and treatment in combination with docetaxel had an even more significant tumor growth inhibitory effect., Conclusion: Anlotinib inhibits the pro-cancer effects of CAFs by suppressing the activation of CAFs and the secretion of pro-cancer cytokines. Our findings suggest that the combination of anlotinib and docetaxel may be a potential strategy for the treatment of refractory cervical cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Xiong, Xu, Zhou, Tong and Yu.)

Primary intraosseous malignant peripheral nerve sheath tumors (MPNSTs) are rare yet highly aggressive neoplasms originating from peripheral nerves. Typically manifesting as soft tissue masses accompanied by pain or functional impairment, these tumors pose significant challenges in management. Surgical intervention remains the cornerstone of treatment for patients with MPNST lacking distant metastasis, with generally modest success rates. In cases of recurrence and metastasis, the pursuit of effective systemic therapies has been a focus of clinical investigation. Herein, we present a case study involving an elderly female patient with refractory MPNST. In light of surgical limitations, a multimodal therapeutic approach combining chemotherapy, denosumab, and subsequent administration of anlotinib was pursued following collaborative consultation. This regimen yielded noteworthy clinical benefits, exemplifying a promising avenue in the management of challenging MPNST cases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Chen, Cui, Zheng, Xu and Yu.)

Introduction: This retrospective study evaluates the efficacy of camrelizumab combined with anlotinib versus chemotherapy in patients with extensive-stage small-cell lung cancer (ES-SCLC) undergoing second-line treatment., Methods: Data were sourced from medical records at a Chinese medical facility, involving 34 patients diagnosed with ES-SCLC after failing first-line treatment. Patients were divided into two groups: one received camrelizumab (200 mg every 3 weeks) with anlotinib (12 mg daily for 14 days followed by a 7-day rest), while the other group received physician-chosen chemotherapy administered every 3 weeks. The primary endpoint was progression-free survival (PFS), with secondary endpoints including overall survival (OS), objective response rate (ORR), and disease control rate (DCR)., Results: The combination therapy group showed a significant improvement in PFS compared to the chemotherapy group (median PFS: 7 months vs. 3 months; hazard ratio (HR): 0.34; 95% confidence interval (CI): 0.15-0.77; p<0.001). However, there was no statistically significant difference in OS between the groups (16.3 months vs. 17.3 months; p=0.82). The ORR was 52.9% in the combination therapy group versus 23.5% in the chemotherapy group (p=0.08), and the DCR was 82.4% compared to 58.8% (p=0.26). Grade 3 or higher adverse events were observed in 17.6% of the combination therapy group and 29.4% of the chemotherapy group., Conclusions: The findings suggest that the combination of camrelizumab and anlotinib offers a superior anti-tumor response with a manageable safety profile in a second-line setting for ES-SCLC patients. This combination regimen may be a viable option for second-line ES-SCLC treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Shen, Li, Guo, Xu and Yan.)

Background: Glomus tumors are typically benign soft tissue tumors that occur at the extremities; malignant and viscerally occurring cases are extremely rare., Case Presentation: We report a 49-year old male patient with a malignant esophageal glomus tumor that was complicated by lung and liver metastases. Genetic test results guided the patient's individualized treatment. Consequently, treatment with Anlotinib combined with Tislelizumab achieved significant clinical benefits., Conclusion: Our case report demonstrates that immunotherapy combined with anti-angiogenic therapy in patients with malignant esophageal glomus tumors can achieve significant efficacy and suggests the potential value of next-generation sequencing (NGS) detection in guiding personalized treatments in patients with malignant esophageal glomus tumors., Competing Interests: Authors JM and CS were employed by the company YuceBio Technology Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Liu, Mao, Shen, Jin, Wu, Song and Du.)

Introduction: Desmoid fibromatosis is an aggressive fibroblastic neoplasm with a high propensity for local recurrence. Targeted therapy for Desmoid fibromatosis represents a novel avenue in systemic treatment. Anlotinib, a novel multitargeted angiogenesis inhibitor, represents a novel approach for targeted therapy. Therefore, this study aims to assess the efficacy and safety of anlotinib in patients with Desmoid fibromatosis., Methods: We retrospectively gathered the clinical medical records of Desmoid fibromatosis patients who underwent anlotinib treatment between June 2019 and November 2023 at our center. Anlotinib was initiated at a daily dose of 12 mg and adjusted based on drug-related toxicity. Tumor response was evaluated using the Response Evaluation Criteria in Solid Tumors 1.1 criteria. Progression-free survival served as the primary endpoint and was analyzed utilizing the Kaplan-Meier method., Results: In total, sixty-six consecutive patients were enrolled. No patients achieved a complete response; however, fourteen patients (21.21%) exhibited a partial response, while forty-six patients (70%) experienced disease stability. Progressive disease was observed in 6 patients (9.10%), and the progression-free survival rates at 12 and 36months were 89.71% and 82.81%, respectively. The disease control rate was 90.91%, while the objective response rate was 21.21%., Conclusion: Anlotinib proves effective in managing recurrent and symptomatic patients with Desmoid fibromatosis. However, the toxicity profile of anlotinib presents a higher risk of Hand-Foot Skin Reaction and hypertension. Therefore, given that 41.67% of patients were subjected to dose adjustments associated with the initial dose of 12 mg, implementing dosage reductions may help balance efficacy with side effects., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Xie, Huang, Gong, Wang, Li, Lu, Luo, Min, Zhou and Tu.)

Background: Based on pharmacoeconomics, drug availability and actual treatment, optimal treatment regimens for Chinese non-small-cell lung carcinoma (NSCLC) patients over 70 years old are needed., Methods: This multicenter, single-arm pilot trial enrolled patients with advanced non-squamous NSCLC who refused systemic chemotherapy. Eligible patients received anlotinib (12 mg/day, d1-14, Q3W) until disease progression, intolerant toxicities, or withdrawal from the study. The primary endpoint was progression-free survival (PFS)., Results: Forty-nine patients were screened between January 2019 and September 2021, of whom 40 patients were eligible. The median age was 76 years. With a median follow-up period of 16.20 (95% CI: 8.77, 25.10) months, the median PFS was 5.45 months (95% CI: 3.52-9.23) and the median overall survival was 10.32 months (95% CI: 6.44-12.78). Three patients achieved a partial response and 34 had stable disease, with an objective response rate of 7.5% and a disease control rate of 92.5%. Thirty-three (82.5%; 33/40) patients reported treatment-related adverse events (TRAEs) of any grade, and the incidence rate of grade ≥3 TRAEs was 35% (14/40). The most common grade ≥3 TRAEs were hypertension (4/40; 10.0%), hand-foot syndrome (3/40; 7.5%), and proteinuria (2/40; 5.0%)., Conclusion: Anlotinib treatment was feasible and safe in Chinese elderly patients with advanced non-squamous NSCLC who did not receive any systemic chemotherapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhao, Li, Hou, Yang, Li, Yan, Li, Liu, Liu, Song, Li, Zhang and Hou.)

Purpose: To investigate the efficacy and safety of combined treatment of anlotinib and transarterial chemoembolization (TACE) in patients with unresectable hepatocellular carcinoma (uHCC) associated with hepatitis B virus (HBV) infection., Methods: We retrospectively collected the data of 96 uHCC patients associated with HBV infection who received either TACE only (TO group; n = 64) or anlotinib combined with TACE (TA group; n = 32) from January 2017 to January 2021. The primary endpoint was overall survival (OS). The secondary outcomes included progression-free survival (PFS), tumor response according to modified Response Evaluation Criteria in Solid Tumors (mRECIST) and RECIST 1.1, and adverse events (AEs)., Results: The median OS and median PFS were significantly longer in the TA group compared to the TO group (17.6 months vs. 9.4 months, p = 0.018; 6.7 months vs. 3.8 months, p = 0.003, respectively). In addition, the overall objective response rate (ORR) and disease control rate (DCR) numerically increased in the TA group (mRECIST, ORR 65.6% vs. 46.9%, p = 0.064, DCR 90.6% vs. 85.9%, p = 0.382; RECIST 1.1, ORR 46.9% vs. 15.6%, p = 0.001, DCR 90.6% vs. 85.9%, p = 0.382, respectively). It was worth noting that no treatment-related mortality occurred during the study. The most common AEs included elevated transaminases (56.3%), decreased appetite (46.9%), and abdominal pain (37.5%) in the TA group. Although the incidence rate of grade 3/4 AEs was higher in the TA group, all of them were controllable., Conclusions: The combination of anlotinib and TACE has shown promising results in improving outcomes for patients with HBV-related uHCC, as compared to TACE monotherapy. In addition, this combination therapy has demonstrated a controllable safety profile. However, further validation is urgently needed through randomized controlled trials with large sample sizes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chen, Cai, Wu, Tang, Chen, Wang, Zhuang and Guo.)

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chen, Zhang, Han, Tang, Guo, Li, Xie, Xu, Zhang, Tian, Pan, Shu, Ma and Chen.)

Background: Anlotinib showed encouraging anti-tumor activity in metastatic colorectal cancer (mCRC). This study was designed to assess the efficacy and safety of anlotinib plus XELOX as first-line therapy in mCRC patients., Materials and Methods: Eligible patients aged ≥18 with mCRC were enrolled in this multicenter, single-arm, phase II, exploratory study. Patients received at least 6 cycles of anlotinib, oxaliplatin, and capecitabine as initial therapy. Subsequently, patients received anlotinib monotherapy as maintenance therapy until tumor progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS)., Results: Thirty-one patients were included between December 2019 and March 2022. The median follow-up was 17.5 (95% CI, 3.0-17.5) months. The median PFS was 8.3 (95% CI, 6.3-10.0) months, with 6- and 12-month PFS rates of 82.3% (95% CI, 59.2%-93.0%) and 18.9% (95% CI, 4.8%-40.1%), respectively. Fifteen (48.4%) achieved partial response for an ORR of 48.4% (95% CI, 30.2%-66.9%). The disease control rate was 71.0% (95% CI, 52.0%-85.8%) due to 7 (22.6%) stable diseases. The median duration of response was 6.0 (95% CI, 3.6-8.0) months and 1 patient had the longest ongoing response of 17.3 months. Of 24 patients with evaluable imaging, 23 (74.2%) obtained tumor shrinkage. The median PFS (11.0 vs. 6.9 months) and ORR (66.7% vs. 60.0%) for patients with RAS/BRAF wild-type were numerically better than those with mutation. Three patients are still ongoing treatment. The grade 3 or more treatment-emergent adverse events (TEAEs) were mainly hypertension (12.9%) and decreased neutrophil count (12.9%). Four (12.9%) had serious TEAEs, primarily including abdominal pain and incomplete intestinal obstruction., Conclusion: Anlotinib plus XELOX as first-line therapy in patients with mCRC showed anti-tumor activity and safety profile, which is worth further investigation., Clinical Trial Registration: chictr.org.cn, identifier ChiCTR1900028417., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Song, Hu, Zhang, Ye, Jin, Shang, Zhang, Sun, Zhang, Yi, Han and Yan.)

Purpose: Anlotinib, a tyrosine kinase inhibitor (TKI) has been in clinical application to inhibit malignant cell growth and lung metastasis in osteosarcoma (OS). However, a variety of drug resistance phenomena have been observed in the treatment. We aim to explore the new target to reverse anlotinib resistance in OS., Materials and Methods: In this study, we established four OS anlotinib-resistant cell lines, and RNA-sequence was performed to evaluate differentially expressed genes. We verified the results of RNA-sequence by PCR, western blot and ELISA assay. We further explored the effects of tocilizumab (anti- IL-6 receptor), either alone or in combined with anlotinib, on the inhibition of anlotinib-resistant OS cells malignant viability by CCK8, EDU, colony formation, apoptosis, transwell, wound healing, Cytoskeletal stain assays, and xenograft nude mouse model. The expression of IL-6 in 104 osteosarcoma samples was tested by IHC., Results: We found IL-6 and its downstream pathway STAT3 were activated in anlotinib-resistant osteosarcoma. Tocilizumab impaired the tumor progression of anlotinib-resistant OS cells, and combined treatment with anlotinib augmented these effects by inhibiting STAT3 expressions. IL-6 was highly expressed in patients with OS and correlated with poor prognosis., Conclusion: Tocilizumab could reverse anlotinib resistance in OS by IL-6/STAT3 pathway and the combination treatment with anlotinib rationalized further studies and clinical treatment of OS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Xu, Chen, Sun, Shi, Wang, Huang, Ren and Tang.)

Objective: The histological conversion of lung adenocarcinoma (LUAD) into small-cell lung cancer (SCLC) is an important resistance mechanism for epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI)-resistant LUAD. Anlotinib has been recommended as the third-line treatment for SCLC patients. The efficacy of etoposide/platinum (EP) as the main treatment is very limited for patients with transformed SCLC. However, little is known about EP plus anlotinib for transformed SCLC. The present study retrospectively explored the clinical response to EP combined with anlotinib in patients with transformed SCLC from LUAD after EGFR-TKI failure., Methods: A total of 10 patients who underwent SCLC transformation from EGFR-TKI-resistant LUAD were retrospectively reviewed from September 1, 2019, to December 31, 2022, in three regional hospitals. All of the patients were treated with the combination regimen of EP and anlotinib for four to six cycles, followed by anlotinib maintenance therapy. The clinical efficacy indices including objective response rate (ORR), disease control rate (DCR), median progression-free survival (mPFS), median overall survival (mOS), and toxicities were evaluated., Results: The median time from EGFR-TKI treatment to SCLC conversion was 20.1 ± 2.76 months (17-24 months). Genetic examination after transformation showed that 90% of the patients retained their original EGFR gene mutations. Additional driver genes were found, including BRAF mutation (10%), PIK3CA mutation (20%), RB1 loss (50%), and TP53 mutation (60%). The ORR and DCR were 80% and 100%, respectively. The mPFS was 9.0 months (95% CI, 7.9-10.1 months), and the mOS was 14.0 months (95% CI, 12.0-15.9 months). Less than 10% of grade 3 toxicities were observed, and no grade 4 toxicity and death events were reported., Conclusion: The EP plus anlotinib regimen appears to be a promising and safe strategy in transformed SCLC patients after EGFR-TKI resistance, which warrants further investigation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Ding, Leng, Gu, Jing and Song.)

Background: Anlotinib is a novel oral small-molecule tyrosine kinase inhibitor (TKI), which can inhibit angiogenesis. The purpose of this study was to evaluate the efficacy and safety of anlotinib combined with chemotherapy in patients with metastatic triple-negative breast cancer (TNBC)., Methods: This phase II clinical trial included 40 patients with metastatic TNBC who had previously received anthracycline and/or taxane treatment. All patients received anlotinib combined with chemotherapy. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR), disease control rate (DCR) and safety., Results: During May 1, 2019 and April 30, 2022, there were 40 patients enrolled in this study. The median PFS and median OS were 8.8 months (95% confidence interval [CI] 6.5-11.1 months) and 19.0 months (95% CI, 12.1-25.9 months), respectively. The ORR, CBR and DCR were 40.0% (16/40), 85.0% (34/40) and 95.0% (38/40), respectively. Cox univariate and multivariate analyses demonstrated that having more than 3 metastatic sites (p = 0.001; p = 0.020) was an independent and meaningful unfavorable prognostic factor for PFS. 37.5% of patients had grade 3 to 4 treatment-related adverse events (TRAEs). The grade 3 to 4 TRAEs included neutropenia (22.5%), leukopenia (20.0%), secondary hypertension (10.0%), hand-foot syndrome (5.0%), vomiting (5.0%), proteinuria (5.0%) and thrombocytopenia (2.5%). None of the patients withdrew from the study or died due to TRAEs., Conclusion: In this single-arm study, the treatment of metastatic TNBC with anlotinib combined with chemotherapy showed certain efficacy, and its toxicity was acceptable., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Huang, Xie, Chen, Zhang, Chen, Bai, Lan, Song, Guo and Du.)

Objective: Exposing tumor antigens to the immune system is the key to ensuring the efficacy of immunotherapy. SBRT is the main way to reveal the specifical antigens of tumors which can enhance the immune response. We aimed to explore the clinical efficacy and safety of Toripalimab combined with Anlotinib for uHCC after SBRT., Methods: This is a prospective, single-arm, explorative clinical study. uHCC patients with an ECOG PS score of 0-1, Child-Pugh class A or B, and BCLC stage B or C were included and treated with SBRT(8Gy*3) followed by 6-cycle combinational therapy with Toripalimab and Anlotinib. The primary endpoint was progression-free survival (PFS) and the secondary endpoints were objective response rate (ORR), disease control rate (DCR), overall survival (OS), and incidence of treatment-related adverse events (TRAEs). Continuous variables were presented as medians and ranges. Survivals were studied with the Kaplan-Meier method. Categorical data were expressed as n (percentage)., Results: Between June 2020 and October 2022, a total of 20 patients with intermediate-advanced uHCC were enrolled. All cases had multiple intrahepatic metastases, or macrovascular invasion, or both, among whom 5 cases with lymph node or distant metastases. Until September 2022, the median follow-up time was 7.2 months (range, 1.1-27.7 months). Median survival time could not be assessed at the moment, based on iRecist, median PFS was 7.4 months (range, 1.1-27.7 months), ORR 15.0%, and DCR 50.0%. 14 patients experienced treatment-related adverse events with an incidence of 70%. The overall survival rates at 18 months and 24 months were 61.1% and 50.9%, respectively. And the progression-free survival rates were 39.3% and 19.7%., Conclusion: Exposure of specific antigens of HCC via SBRT may improve the efficacy of combinational therapy with Toripalimab and Anlotinib for uHCC with manageable adverse effects, which deserves further exploration., Clinical Trial Registration: www.clinicaltrials.gov, identifier ChiCTR2000032533., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chen, Hong, Fang, Zhang, Luo, Chen, Yu, Fan, Chi and Peng.)

Background: Efficacy and toxicities of anlotinib (ANL) show large inter-patient variation, which may partly be explained by differences in ANL exposure. Exposure-response/toxicities relationship have not been investigated for ANL. Therefore, the aim of the present study was to explore the association between the trough plasma concentration (C trough ) of ANL and treatment outcomes in Chinese patients with advanced non-small cell lung cancer (NSCLC)., Methods: Patients with advanced NSCLC who started third-line or further ANL alone therapy between January 2021 and October 2022. This study examined the ANL C trough and clinical response evaluation at day 43 after initiation of ANL treatment. We evaluated the association between the ANL C trough and clinical efficacy and toxicities. Additionally, this study defined patients with complete response (CR), partial response (PR) and stable disease (SD) as responder. The receiver-operating characteristic (ROC) curve combined with Youden index was identify the potential threshold value of ANL C trough for the responder., Results: 52 patients were evaluated for analyses. The median ANL C trough was 11.45ng/ml (range, 3.69-26.36 ng/ml). The ANL C trough values in the PR group (n=6, 15.51 ng/ml (range, 8.19-17.37 ng/ml)) was significantly higher than in the PD group (n=8, 7.44 ng/ml (range, 5.41-14.69 ng/ml), p =0.001). The area under the ROC curve (AUC ROC ) was 0.76 (95% confidence interval (CI), 0.58-0.93; p =0.022) and threshold value of ANL C trough predicting responder was 10.29 ng/ml (sensitivity 65.9% and specificity 87.5%, the best Youden index was 0.53). The disease control rate (DCR) was 84.6%, and DCR was significantly higher in the high-exposure group (≥10.29ng/ml) than low-exposure group (<10.29ng/ml) (96.67% vs 68.18%, p =0.005). Although there was no significant difference in ANL C trough between grade ≥ 3 and grade ≤2 toxicities, the incidence of any grade hand-foot syndrome (70.0% vs 36.36%, p =0.016) and thyroid-stimulating hormone elevation (53.33% vs 22.73%, p =0.026) was significantly higher in the high-exposure group compared with the low-exposure group., Conclusions: Considering these results, we propose that maintaining ANL C trough ≥ 10.29ng/ml was important for achieving the response in advanced NSCLC patients treated with ANL., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chen, Jiang, Rao, Wang, Yan, Ye and Lou.)

Introduction: Anlotinib, a novel multi-kinase inhibitor, was found to improve progression-free survival (PFS) in brain metastases., Methods: This paper retrospectively analyzed 26 newly diagnosed or recurrent high-grade gliomas from 2017 to 2022, and the patients received oral anlotinib during concurrent postoperative chemoradiotherapy or after recurrence. Efficacy was evaluated according to the Response Assessment in Neuro-Oncology (RANO) criteria, and the main study endpoints were PFS at 6 months and overall survival (OS) at 1 year., Results: After the follow-up, until May 2022, 13 patients survived and 13 patients died, with a median follow-up time of 25.6 months. The disease control rate (DCR) was 96.2% (25/26), and the overall response rate (ORR) rate was 73.1% (19/26). The median PFS after oral anlotinib was 8.9 months (0.8-15.1), and the PFS at 6 months was 72.5%. The median OS after oral anlotinib was 12 months (1.6-24.4), and the OS at 12 months was 42.6%. Anlotinib-related toxicities were observed in 11 patients, mostly grades 1-2. In the multivariate analysis, patients with Karnofsky Performance Scale (KPS) above 80 had a highermedian PFS of 9.9months (p = 0.02), and their sex, age, IDH mutation, MGMTmethylation, and whether anlotinib was combined with chemoradiotherapy or maintenance treatment had no effect on PFS., Conclusion: We found that anlotinib combined with chemoradiotherapy in treating high-grade central nervous system (CNS) tumors can prolong PFS and OS and that it was safe., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest., (Copyright © 2023 Shen, Li, Liu, Sun, Qiu, Ding and Sun.)

Background: Anlotinib may boost the efficacy of pancreatic cancer (PC) treatment if timely added to the GS regimen (Gemcitabine, Tegafur-gimeracil-oteracil potassium); however, no data has been published. This study evaluated the safety and efficacy of anlotinib in combination with the GS regimen(hereafter referred to as the A+GS regimen) in the first-line treatment of patients with unresectable or metastatic PC., Methods: Patients with unresectable or metastatic PC treated at Yueyang Central Hospital and Yueyang People's Hospital between October 2018 and June 2022 were enrolled in this retrospective real-world investigation. Treatment efficacy was evaluated based on the overall survival (OS), progression-free survival (PFS), disease control rate (DCR), and objective response rate (ORR), while the treatment safety was assessed by the frequency of major adverse events (AEs)., Results: Seventy-one patients were included in this study, 41 in the GS group and 30 in the A+GS group. The A+GS group had a longer mPFS than the GS group (12.0 months (95% CI, 6.0-18.0) and 6.0 months (95% CI, 3.0-8.1)), respectively (P = 0.005). mOS was longer in the GS+A group) when compared with the GS group (17.0 months (95%CI, 14.0-20.0) and 10.0 months (95% CI, 7.5-12.5)), respectively (P = 0.018). The GS+A group had higher ORR (50.0% vs 26.8%, P = 0.045) and DCR (83.3% vs 58.5%, P = 0.026). Furthermore, there were no grade 4-5 AEs and no treatment-related deaths, and no discernible increase in AEs in the GS+A group when compared with the GS group., Conclusion: The A+GS regimen therapy holds great promise in managing treatment-naive advanced PC, except that future prospective studies with larger sample sizes and multiple centers are required to determine its efficacy and safety., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhan, Hu, Da, Weng, Zhou, Wen, Liu, Fang, Shen, Zhou, Luo, Xu, Zhan and Su.)

Objective: To evaluate the efficacy and safety of anlotinib-based treatment in metastatic breast cancer (MBC) patients with failure of standard treatment., Methods: We collected the medical data of 56 female patients with the diagnosis of MBC and had failed the standard treatment before. These patients received at least two cycles of anlotinib-based treatment as the second-line or beyond treatment between October 2019 and April 2022 in Jiangsu Cancer Hospital. The primary endpoint of our study was progression-free survival (PFS), and it was estimated with Kaplan-Meier. The second end points were disease control rate (DCR), objective response rate (ORR), and side effects., Results: The median PFS time of a total of 56 patients was 5.7 months (95% CI, 3.17-8.22months). The ORR and DCR was 28.6% and 71.4%, respectively. In second-line, third-line, and beyond treatment, the median PFS was 11.7 months, 8.7 months, and 4.7 months, respectively. In different subtype of breast cancer, the median PFS was 5.6 months, 5.7months, and 6.4 months in human epidermal growth factor receptor 2 positive (HER2+), hormone receptor positive and HER2 negative (HR+/HER2-), and triple negative breast cancer (TNBC) patients, respectively. Most adverse effects were clinically manageable, and the most common events were platelet count decrease (35.7%), hand-foot syndrome (19.6%), diarrhea (19.6%), and fatigue (17.9%). The most common grade 3 and 4 adverse events were platelet count decrease (25.0%), diarrhea (7.1%), and oral mucositis (5.4%)., Conclusion: Anlotinib-based treatment showed good efficacy and manageable toxicity in multi-line treatment of MBC patients who failed the standard treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Qian, Lou, Zhou, Zhang and Yuan.)

Background: Medullary thyroid carcinoma (MTC) is a rare type of thyroid cancer; however, it accounted for 13.4% of the disease-specific mortalities. ALTER01031 (NCT02586350) was a randomised, placebo-controlled phase 2b trial that evaluated the efficacy and safety of anlotinib in locally advanced or metastatic MTC. This post hoc analysis aimed to evaluate the efficacy and safety of anlotinib in older patients and those with bone metastases using ALTER01031., Methods: In ALTER01031, anlotinib significantly prolonged the median progression-free survival (PFS) from 11.1 months to 20.7 months compared with placebo in the whole population. Patients who were older (≥ 50 years) or had bone metastases were selected. PFS and overall survival (OS) were estimated and compared between patients receiving anlotinib or placebo in each subgroup. A sub-analysis of tumour response and safety was also performed., Results: Patients with older age or bone metastases experienced rapid disease progression as the median PFS was 6.8 months and 7.0 months respectively in the placebo group. Anlotinib significantly improved the median PFS to 17.5 months ( P = 0.002) and 20.7 months ( P = 0.029) with hazard ratio (HR) of 0.31 (95% CI, 0.15-0.68) and 0.44 (95% CI, 0.20-0.94) compared with placebo. Significant benefit in OS was observed in patients with older age after a longer follow-up (HR = 0.47 [95% CI, 0.22-0.99], P = 0.041). The safety profile of these subgroups was similar to that of the entire population., Conclusion: This sub-analysis demonstrated significant survival benefits and favourable safety of anlotinib in patients with MTC who had old age or bone metastases, supporting the feasibility of anlotinib in these patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zhao, Chi, Hu, Chen, Ge, Zhang, Guo, Wang, Chen, Zhang, Cheng, Li, Liu, Qin, Zhu, Cheng, Xu, Li, Tang, Gao and Zheng.)

Background: Pulmonary sarcomatoid carcinoma (PSC) is a rare and aggressive disease without standardized treatment strategies. The efficacy of second-line or beyond immune checkpoint inhibitors (ICIs) has been proven in recent studies, whereas the evidence for first-line immunotherapy for PSC is still limited to case reports and remains poorly understood., Materials and Methods: This was a multicenter, retrospective analysis of 21 patients with a histological diagnosis of PSC who received ICI as first-line therapy from January 2019 to March 2022. The expression of PD-L1 was evaluated by immunohistochemistry (IHC) using the monoclonal antibody 22C3. Low and high PD-L1 expressions were defined using the tumor proportion score (TPS), with cutoffs of 1 and 50%, respectively., Results: All eight patients had PD-L1 positivity who underwent PD-L1 expression assessment, and six patients (6/8, 75.0%) had high PD-L1 expression. Among the 21 PSC patients, seven received tislelizumab, six received camrelizumab, four received sintilimab, three received pembrolizumab, and one received durvalumab. Among them, 18 PSCs received combination therapy, whereas another three PSCs received immunotherapy alone. Out of the 21 PSC patients, 12 (57.1%) achieved a partial response (PR), and five patients had stable disease (SD) as the best response, whereas four PSCs experienced dramatic progressive disease (PD). The median progression-free survival (PFS) was 9.2 (95% CI [4.3, 14.1]) months, and the median OS was 22.8 (95% CI [4.0, 41.5]) months. Among the three treatment groups (immunotherapy alone, immunotherapy combined with anlotinib, and chemoimmunotherapy), the median PFS was 8.0, 9.4, and 9.6 months, and the median OS was 19.0, 22.8, and 30.6 months, respectively. There was no difference in PFS and OS between the three treatment regimen groups ( P = 0.86 and P = 0.34, respectively) and different immunotherapies ( P = 0.10 and P = 0.23, respectively). No serious adverse events (grade ≥ 3) were noted., Conclusion: First-line immunotherapy has promising therapeutic potential in the treatment of PSC. More studies are warranted to confirm these findings., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Qian, Wang, Liu, Yuan, Fang, Zhang, Yuan, Chen, Yu, Wang, Yin and Li.)

Background: To evaluate the potential treatment for patients with non-small cell lung cancer (NSCLC) and rare malignant pulmonary lymphangitis carcinomatosis (PLC), our study provided a genomic profile and clinical outcome of this group of patients., Methods: We retrospectively reviewed patients with NSCLC who developed PLC. The genomic alterations, tumor mutation burden (TMB), and microsatellite instability (MSI) based on DNA-based next-generation sequencing were reviewed and compared in a Chinese population with lung adenocarcinomas (Chinese-LUAD cohort). Clinical outcomes after exploratory anlotinib treatment and factors influencing survival are summarized., Results: A total of 564 patients with stage IV NSCLC were reviewed, and 39 patients with PLC were included. Genomic profiling of 17 adenocarcinoma patients with PLC (PLC-LUAD cohort) revealed TP53 , EGFR , and LRP1B as the three most frequently altered genes. EGFR was less mutated in PLC-LUAD than Chinese-LUAD cohort of 778 patients (35.3% vs. 60.9%, P = 0.043 ). BRIP1 was mutated more often in the PLC-LUAD cohort (11.8% vs. 1.8%, P= 0.043 ). Two patients presented with high tumor mutational burden (TMB-H, 10 mutations/MB). Combing alterations in the patient with squamous cell carcinoma, the most altered pathways of PLC included cell cycle/DNA damage, chromatin modification, the RTK/Ras/MAPK pathway and VEGF signaling changes. Fourteen of the participants received anlotinib treatment. The ORR and DCR were 57.1% and 92.9%, respectively. Patients achieved a median progression-free survival of 4.9 months and a median overall survival of 7 months. The adverse effects were manageable. In patients with adenocarcinoma, the mPFS (5.3 months vs. 2.6 months) and mOS (9.9 months vs. 4.5 months) were prolonged in patients receiving anlotinib treatment compared to those receiving other treatment strategies ( P < 0.05 )., Conclusion: Patients with PLC in NSCLC demonstrated distinct genetic alterations. The results improve our understanding of the plausible genetic underpinnings of tumorigenesis in PLC and potential treatment strategies. Exploratory anlotinib treatment achieved considerable benefits and demonstrated manageable safety., Competing Interests: Authors SL, LZ, DC, YQ and MX were employed by the company Jiangsu Simcere Diagnostics Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Dong, Cheng, Zhang, Li, Zhao, Chen, Qin, Xiao and Fang.)

Background: Patients with extensive-stage small-cell lung cancer (ES-SCLC) have high recurrence rates and bleak prognosis. This multicenter real-world study aimed to explore the efficacy and safety of anlotinib combined with platinum-etoposide chemotherapy as the first-line treatment of ES-SCLC., Methods: Pathologically confirmed ES-SCLC patients receiving anlotinib plus platinum-etoposide chemotherapy as the first-line treatment were enrolled in this retrospective study. The primary endpoint of this study was progression-free survival (PFS), and secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and adverse reactions. The Cox regression analyses were employed to investigate the independent prognostic factors for OS and PFS of these individuals., Results: In total, 58 patients were included in this study. The median PFS was 6.0 months [95% confidence interval (CI): 3.5-8.5], and the median OS was 10.5 months (95%CI 8.7-12.3). Thirty-four patients achieved partial response (PR), 18 patients achieved stable disease (SD), and 6 patients achieved progressive disease (PD). The ORR and DCR were 58.6% and 89.6%. The main treatment-related adverse reactions were generally tolerated. Myelosuppression (44.8%) was the most common adverse reaction, followed by hypertension (41.4%), fatigue (34.5%), gastrointestinal reaction (32.7%), and hand-foot syndrome (24.1%). Multivariate analysis showed that post-medication hand-foot syndrome [PFS 8.5 vs. 5.5 months, Hazards Ratio (HR)=0.23, 95%CI 0.07-0.72, P =0.012] was the independent predictor of PFS, and hypertension (OS 15.9 vs. 8.3 months, HR=0.18, 95%CI 0.05-0.58, P =0.005) was the independent predictor of OS., Conclusion: Anlotinib combined with platinum-etoposide chemotherapy as the first-line treatment for ES-SCLC appears to be effective and well-tolerated in the real-world. Well-designed large-scale prospective studies are urgently needed in the future to verify our findings., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zheng, Jiang, Gao, Liu, Zheng, Fu, Ruan, Tian, Liang and Yao.)

Background: Both anlotinib and programmed death-1 (PD-1) blockade have been approved for the second-line treatment of metastatic esophageal squamous cell carcinoma (ESCC). However, the combination of these two therapies has not been evaluated. This study investigated the efficacy and safety of anlotinib, a novel multitarget tyrosine kinase inhibitor targeting tumor angiogenesis, combined with PD-1 blockade as second or further-line treatment for advanced ESCC., Methods: Between January 2019 and February 2021, 98 advanced ESCC patients receiving anlotinib plus PD-1 blockade or anlotinib monotherapy as second or further-line treatment at Henan Cancer Hospital were retrospectively analyzed. Patients receiving anlotinib plus PD-1 blockade were grouped as cohort A (n=48), while those receiving anlotinib monotherapy were grouped as cohort B (n=50). The primary endpoint was progression-free survival (PFS). Secondary endpoints included the objective response rate (ORR), disease control rate (DCR) and toxicity. Furthermore, independent prognostic factors were identified by Cox regression analysis. A two-sided p-value of <0.05 was considered statistically significant., Results: Data was collected until May 1, 2021, with a median follow-up time of 9.30 months (8.23-10.37 months) in cohort A and11.10months (7.82-14.38 months) in cohort B. For patients with advanced ESCC, cohort A resulted in significantly longer PFS (5.40 vs. 3.00 months, P<0.001) and higher DCR (71.7% vs. 47.9%, P=0.019) than cohort B. The ORR indicated no significant difference between cohort A (23.9%) and cohort B (10.4%) (P=0.082). Adverse reactions were mainly grade1/2 in the two groups. Compared with cohort B, a significantly higher rate of grade 1-2 hypothyroidism was observed in patients in cohort A (P= 0.034). Three patients (6.3%) developed grade 1/2 immune-related pneumonia. There was no significant difference in the incidence of grade 3-4 toxicities. Multivariable Cox regression analysis showed that the drug regimen (P<0.001), Eastern Cooperative Oncology Group Performance Status (P=0.002), distant organ metastasis (P=0.008), and metastatic sites (P=0.032) were independent prognostic factors for PFS., Conclusions: Anlotinib plus PD-1 blockade showed promising anti-tumor activity and manageable toxicity as second or further-line treatment of advanced ESCC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Liu, Ge, Xu, Li and Liu.)

Anlotinib is a new multitarget tyrosine kinase inhibitor for tumor angiogenesis, and its monotherapy exhibits a decent clinical efficacy. However, the process of combining Anlotinib and immune checkpoint therapy to achieve optimal antitumor effects while limiting side effects remains unclear. In this study, we found that effective low-dose Anlotinib was sufficient to inhibit tumor growth while reducing side effects compared with high doses. Effective low-dose Anlotinib treatments induced durable tumor vascular normalization and improved anti-PD-1 therapy in both short- and long-term treatment regimens. Mechanistically, the combination therapy increased the proportions of intratumoral CD4 + T, CD8 + T, and NK cells. Anlotinib-associated antitumor effects were independent of interferon γ; however, the combination therapy required CD8 + T cells to suppress tumor growth. Together, these results suggest that the combination of effective low-dose Anlotinib and PD-1 blockade induces durable antitumor effects with fewer side effects. Our findings indicate that antiangiogenic treatments combined with immune checkpoint therapy at an effective low-dose, rather than a tolerable high dose, would be more efficacious and safer., Competing Interests: Authors XW and WX were employed by Innovent Biologics Inc. (Suzhou, China). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Fan, Qiang, Liu, Zhao, Wang, Liu, Wang, Chu, Huang, Xu and Qin.)