Efficacy and safety of anlotinib for the treatment of advanced bone and soft tissue sarcomas: a systematic review and meta-analysis

Background: Sarcoma, a rare and highly heterogeneous malignant neoplasm originating from mesenchymal tissues, is broadly classified into bone sarcoma and soft tissue sarcoma depending on where they occur. Patients with advanced or metastatic sarcomas face a poor prognosis. Conventional chemotherapy regimens demonstrate limited efficacy with substantial adverse effects, and therapeutic options remain scarce for those experiencing chemotherapy failure or intolerance. The development of tyrosine kinase inhibitors has brought the treatment of sarcoma into a new stage. As a multi-target tyrosine kinase inhibitor, anlotinib exerts antitumor effects through dual mechanisms of anti-angiogenesis and direct tumor cell proliferation inhibition. While it has been increasingly reported to treat bone and soft tissue sarcoma with promising efficacy, there has been no systematic analysis of this application.

Methods: PubMed, Embase, the Cochrane Library, Web of Science, Vip (China), Cnki (China), WanFang (China), and SinoMed (China) databases were systematically searched for relevant studies, published from the inception of each database to July 12, 2025, without language restrictions. The primary outcomes included the objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs). These data were extracted and analyzed using STATA 17.0 software.

Results: A total of 16 studies with 787 participants were included in this meta-analysis. In terms of clinical efficacy, the pooled outcomes indicated that ORR and DCR were 8.8% (95%CI: 6.2%–11.7%) and 70.7% (95%CI: 64.8%–76.2%), respectively. Median PFS ranged from 2.7 to 12.4 months, with a pooled result of 6.68 months (95%CI: 5.37–7.98). Median OS ranged from 11.4 to 42 months, with a mean of 19 ± 9.5 months. Furthermore, the 3-, 6-, and 9-month PFS rates were 71.1%, 48.4%, and 32.0%, respectively. The 6- and 12-month OS rates were 85.7% and 67.8%, respectively. With regard to clinical safety, the three most common all-grade treatment-related adverse events associated with anlotinib were hand-foot syndrome (34.7%), hypertension (32.4%), and pharyngalgia (30.6%). However, the incidence of grade 3–4 adverse events was relatively low and manageable; for example, hypertension (7.9%), hand-foot syndrome (2.9%), and pneumothorax (3.0%).

Conclusions: Based on the evidence provided by this meta-analysis, anlotinib demonstrates promising clinical efficacy and a favorable safety profile in patients with advanced bone and soft tissue sarcomas, although additional high-quality clinical studies are required to further evaluate its properties and toxicity.

Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/view/CRD420251103981, PROSPERO.

Introduction

Sarcomas are a heterogeneous group of mesenchymal malignancies, which can be broadly classified into bone sarcoma and soft tissue sarcoma depending on where they occur (1). They comprise more than 70 histological subtypes with heterogeneous and diverse features in their clinical, pathological, and biological aspects, as well as in their treatment and prognosis (2). Although complete tumor resection with a sufficient surgical-margin is the most effective primary therapy for early sarcomas, 30–50% of sarcomas eventually recur or metastasize after surgery, and some patients present with metastases at the initial diagnosis (3, 4). For patients with advanced, refractory, metastatic, or relapsed bone and soft tissue sarcomas, the prognosis is poor and doxorubicin-based systemic chemotherapy is preferred as first-line treatment (5). However, the five-year survival of chemotherapy ranges between 15 and 30%, with a median overall survival of 1.5–2 years (6). Furthermore, the long-term use of anthracyclines and other cytotoxic drugs is associated with an increased risk of cardiomyopathy (7). Hence, it is urgent to explore new methods to improve long-term disease control and overall survival for advanced bone and soft tissue sarcoma.

As a prerequisite for invasive tumor growth and metastasis, angiogenesis is a key control point in tumor progression (8). Anti-angiogenic therapy was not only an initial strategy in the targeted treatment of sarcoma but also remains its foundation today (9). Vascular endothelial growth factor (VEGF) is a major driver of angiogenesis and plays a crucial role in tumor growth, metastasis, and invasion (10). Besides, dysregulation of the FGF/FGFR signaling pathway facilitates cancer progression and augments the angiogenic potential of the tumor microenvironment (11). In addition, platelet-derived growth factor (PDGF) and c-Kit, critical mediators of cellular proliferation, have emerged as attractive drug targets, offering a potential new strategy for treating advanced bone and soft tissue sarcoma (12).

Anlotinib (AL3818) is a novel, orally available, and highly potent multi-targeted tyrosine kinase inhibitor. It selectively inhibits VEGFR-2/3 and FGFR-1–4 with high affinity, thereby blocking VEGF-driven signaling pathways. Furthermore, anlotinib suppresses tumor proliferation by targeting additional kinases, including PDGFRα/β, c-Kit, Ret, c-FMS, Aurora-B, and DDR (13). Exhibiting promising efficacy and manageable toxicity in various cancers, anlotinib was recommended for several types of solid tumours including advanced soft tissue sarcoma, non-small cell lung cancer, and medullary thyroid carcinoma (14–16).

Although a number of studies have reported the efficacy and safety of anlotinib in the treatment of sarcoma, due to the low incidence of bone and soft tissue sarcoma, most of studies are non-randomized controlled trials with small sample sizes or uncontrolled statistical analysis and inconsistent outcome indicators. Therefore, this meta-analysis aims to comprehensively evaluate the efficacy and safety of anlotinib in the treatment of advanced bone and soft tissue sarcoma, providing more options for clinical treatment.

Materials and methods

Search strategy

This systematic review and meta-analysis was conducted following a rigorous experimental protocol that was prospectively registered on the PROSPERO platform (https://www.crd.york.ac.uk/PROSPERO/view/CRD420251103981). A total of eight databases (PubMed, Embase, the Cochrane Library, Web of Science, Vip, Cnki, WanFang, and SinoMed) were systematically searched for relevant studies, published from the inception of each database to July 12, 2025, without language restrictions. We adopted a search strategy combining MeSH and free words, and the main terms used were as follows: “Sarcoma”, “Soft Tissue Sarcoma”, “Epithelioid Sarcoma”, “Spindle Cell Sarcoma”, “Anlotinib”, “AL3818”, “Catequentinib”, and “Anlotinib Hydrochloride”. Finally, a manual search of the reference lists from all included studies was conducted to identify additional relevant studies.

Study selection

Studies were included if they met the following inclusion criteria: 1) Enrolled patients were histologically diagnosed with bone or soft tissue sarcoma; 2) Oral anlotinib at a dose of 12 mg once daily from days 1 to 14 every 3 weeks was the intervention, whatever previous treatment regimen was; 3) Patients were reported with interested clinical efficiency outcomes, including objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS); 4) All grades of adverse events (AEs) related to the treatment are the primary safety outcomes; 5) All types of clinical research, including prospective clinical trials and retrospective analysis, can be considered.

Studies were excluded if they met any of the following exclusion criteria: 1) Non-eligible publications(e.g.,laboratory research, animal experiments, reviews, meta-analyses,editorial comments,case reports,meeting abstracts or letters); 2) Duplicate publications or with incomplete data; 3) Sample sizes were less than ten cases; 4) Patients received combination medication during the period of anlotinib administration. To avoid selection bias, two reviewers independently identified potentially eligible articles through the predefined eligibility criteria. Any disagreements were resolved through discussion, with a final decision made by a third reviewer.

Data extraction

Data extraction from the included studies was conducted independently by two authors using a standardized Microsoft Excel spreadsheet. To ensure the reliability of the extracted data, discrepancies were adjudicated by a third author through an independent review and discussion. The information we extracted from included studies was summarized as follows: 1) Article details: first author, publication year, study period, and study type; 2) Participant characteristics: sample size, gender, age, median follow-up, prior therapeutic regimen and histopathological diagnosis; 3) Anlotinib dosing and administration; 4) Clinical efficacy and safety outcomes: ORR, DCR, OS, PFS, and the incidence of AEs related to anlotinib administration by grade.

Quality assessment

The Methodological Index for Non-randomized Studies (MINORS) was used to evaluate the quality of including non-controlled trials (17). The MINORS instrument comprised 12 items, each scored from 0 to 2. The first eight items were applicable for assessing the methodological quality of all studies, regardless of the presence of a control group. In addition, the methodological quality of the included retrospective studies was assessed using the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Case Series, which comprises ten items (18). Two investigators independently evaluated the quality and level of evidence for eligible studies, and any discrepancy was resolved through discussion.

Statistics analysis

All statistical analyses were performed using Stata software (version 17.0; StataCorp, College Station, TX, United States). To synthesize the endpoint data, we conducted a random effect meta-analysis using the metaprop_one command in Stata, a method which accommodates studies with zero event rates (19). The Freeman-Tukey double arcsine transformation was applied to compute the weighted pooled proportions and their 95% confidence intervals (CIs), which were then back-transformed for interpretation and presented using forest plots. Heterogeneity was assessed using Cochran’s Q test and the I² statistic, with a p-value < 0.10 and I² > 50% indicating substantial heterogeneity. Moreover, subgroup analysis was stratified based on tumor type, comparing bone sarcoma with soft tissue sarcoma. Finally, we conducted sensitivity analysis and assessed publication bias using Egger’s test and funnel plots to evaluate the robustness of the pooled results and identify potential bias.

Result

Study selection

We conducted a comprehensive literature search across eight databases in accordance with the predefined search strategy, obtaining 1069 records. Following the removal of duplicates and initial screening of titles and abstracts, 93 potentially eligible articles were identified. Finally, after full-text review of these articles, a total of sixteen studies (20–35), comprising 787 patients, fulfilled the eligibility criteria and were included in the final meta-analysis. Figure 1 presents a detailed flowchart illustrating the study selection process.

Figure 1

Figure 1. Literature selection flowchart and search yields from individual databases. (PubMed, n=53; EMbase, n=433; Cochrane Library, n=25; Web of Science, n=196; CNKI, n=69; VIP, n=112; WanFang Data, n=106; SinoMed, n=75).

Study characteristics and quality assessment

Of the 16 included studies, six were prospective clinical trials and ten were retrospective analysis. Eight studies focused exclusively on soft tissue sarcomas, three solely involved bone sarcomas, and the remaining five included both types. Among soft tissue sarcomas, the three most common pathological subtypes are synovial sarcoma, leiomyosarcoma, and liposarcoma. In contrast, among primary bone sarcomas, the most prevalent types are osteosarcoma, chondrosarcoma, and Ewing’s sarcoma.The total study population comprised 787 patients, with a male-to-female ratio of 1:1.15 and a mean median age of 40.4 years (range, 13–65). All patients received anlotinib monotherapy at 12 mg/day initially, administered in 3-week cycles (2 weeks on, 1 week off). Dose reduction to 10 mg/day or 8 mg/day was implemented for grade 3–4 treatment-related adverse events. Treatment was discontinued due to disease progression, death, or intolerable toxicity. Detailed characteristics of the included studies are summarized in Table 1. Additionally, we assessed the methodological quality of the included studies using tools appropriate to each study design. The six non-randomized controlled trials were evaluated with the MINORS instrument, while the ten retrospective case series were appraised using the JBI critical appraisal checklist. Overall, all studies were rated as having moderate to high methodological quality. Detailed results of the quality assessment are presented in Table 2 and Table 3.

Table 1

Table 1. The main characteristics of included studies.

Table 2

Table 2. Quality assessment of included non-randomized controlled trials.

Table 3

Table 3. Quality assessment of included retrospective studies.

Tumor response and survival

All studies included in this meta-analysis reported the efficacy response of anlotinib in patients with advanced bone and soft tissue sarcomas. Owing to significant heterogeneity among the studies, a random-effects model was applied for the analysis. The pooled ORR was 8.8% (95% CI: 6.2%–11.7%), and DCR was 70.7% (95% CI: 64.8%–76.2%) (Figure 2). Additionally, all included studies reported survival outcomes. Among these, 16 studies provided data on PFS, and 11 studies also reported OS. The reported median PFS across studies ranged from 2.7 to 12.4 months. The pooled median PFS was 6.68 months (95% CI: 5.37–7.98), with 3−, 6−, and 9−month PFS rates of 71.1%, 48.4%, and 32.0%, respectively (Figure 3). For overall survival, the median OS ranged from 11.4 to 42.0 months, with a mean of 19.0 ± 9.5 months. The pooled 6−month and 12−month OS rates were 85.7% and 67.8%, respectively (Figure 4).

Figure 2

Figure 2. Forest plot of the pooled results for ORR (A) and DCR (B) across histology subgroups. ORR, objective response rate; DCR, disease control rate.

Figure 3

Figure 3. Forest plot of the pooled results for median PFS (A) and 3-, 6-, and 9-month PFS rates (B-D) across histology subgroups. PFS, progression-free survival.

Figure 4

Figure 4. Forest plot of the pooled results for 6- and 12-month OS rates (A, B) across histology subgroups. OS, overall survival.

Incidence of adverse events

The severity of adverse events was assessed according to the Common Terminology Criteria for Adverse Events (CTCAE). All included studies reported treatment-related AEs, four of which exclusively reported events of grade≥3. We extracted and pooled the incidence of adverse events to systematically evaluate the safety profile of anlotinib in the treatment of bone and soft tissue sarcomas, with detailed data presented in Table 4. The pooled results indicated that the three most commonly reported adverse events were hand-foot syndrome (34.7%, 95% CI: 22.1%–48.3%), hypertension (32.4%, 95% CI: 21.8%–44%), and pharyngalgia (30.6%, 95% CI: 21.5%–40.4%). Diarrhea, fatigue and hypothyroidism were also reported relatively frequently, with incidence rates exceeding 20%. The incidence of grade≥3 AEs was substantially lower, with all reported types occurring in less than 10% of patients, including hypertension (7.9%, 95%CI: 4.7%–11.7%), hand-foot syndrome (2.9%, 95%CI: 1.1%–5.4%), and pneumothorax (3.0%, 95%CI: 1.1% – 5.6%). Furthermore, no permanent morbidity was reported, and all adverse events were effectively managed via drug interruption, dose adjustment, or symptomatic therapy.

Table 4

Table 4. The pooled incidence of adverse events from the included studies.

Subgroup analysis

We performed subgroup analyses according to histological subtypes. Among the included studies, nine focused specifically on soft tissue sarcoma(STS) and four on bone sarcoma. The results of subgroup analysis indicated that the ORR and DCR for patients with STS were 9% (95% CI: 5.4%–13.4%) and 71.6% (95% CI: 62.8%–79.6%), respectively, compared to 9.6% (95% CI: 4.5%–16.2%) and 68% (95% CI: 50.0%–83.8%) for those with bone sarcoma. Similarly, survival outcomes were also analyzed in both subgroups. The median PFS was 6.7 months (95% CI: 5.7–7.6) in the STS group and 5.7 months (95% CI: 1.2–10.3) in the bone sarcoma group. The 3-month PFS rate was 71.7% (95% CI: 64.1%–78.8%) for STS and 72.3% (95% CI: 57.0%–85.5%) for bone sarcoma; the 6-month PFS rates were 51.5% (95% CI: 42.5%–60.4%) and 38.2% (95% CI: 18.9%–59.4%), respectively; and the 9-month PFS rate was 33.3% (95% CI: 28.7%–38.0%) for STS and 21.8% (95% CI: 6.6%–41.6%) for bone sarcoma. Additionally, we summarized and compared overall survival (OS) and the incidence of common adverse events between the two subgroups. Detailed results of the subgroup analyses are presented in Table 5.

Table 5

Table 5. The pooled results of subgroup analysis.

Sensitivity analysis and publication bias

To evaluate the robustness of the meta-analysis, we performed a sensitivity analysis by omitting one study at a time to assess its effect on the pooled results. This analysis revealed that no single study significantly altered the overall pooled results or their 95% CIs, indicating the statistical robustness of the meta-analysis results. Furthermore, publication bias was assessed for the primary outcomes through funnel plots and Egger’s regression test. The results demonstrated no evidence of substantial publication bias, supporting the validity of the meta-analytic conclusions.

Discussion

Currently, targeted therapy can be employed as either first- or second-line treatment for certain advanced solid tumors. Among these, targeted agents, particularly anti-angiogenic tyrosine kinase inhibitors (AA-TKIs), have demonstrated comparative advantages in terms of individualized treatment and safety profiles, thereby offering novel therapeutic strategies for oncology treatment.

By targeting multiple signaling pathways, including VEGF, fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), FMS-like tyrosine kinase (FLT), rearranged during transfection (RET), and c-Kit, AA-TKIs exert anti-tumor effects via the induction of tumor vascular regression and the suppression of angiogenesis (36, 37). With the advancing understanding of the mechanisms underlying sarcoma pathogenesis, potential targets involved in its pathogenesis are increasingly being identified (38). Furthermore, numerous clinical trials have resulted in the increasing use of AA-TKIs in neoadjuvant or combination therapy regimens for sarcoma patients. For those with advanced sarcoma who are not amenable to surgical resection or are refractory to chemotherapy, AA-TKIs can effectively delay disease progression and convert unresectable bone and soft tissue sarcomas into resectable tumors (39).

Anlotinib is an orally administered multi-targeted TKI that exerts antitumor effects through the simultaneous inhibition of tumor angiogenesis and tumor cell proliferation by selectively targeting FGFR, VEGFR, PDGFR, RET, and c-Kit (40). According to the 2019 Chinese Society of Clinical Oncology (CSCO) guidelines, anlotinib is recommended as a second-line treatment for advanced or refractory soft tissue sarcoma, and may also be used as a first-line therapy for advanced alveolar soft part sarcoma and clear cell sarcoma. A randomized, double-blind, placebo-controlled, multicenter phase IIb trial (ALTER0203, NCT02449343) enrolled 233 patients to evaluate the efficacy of anlotinib in advanced soft tissue sarcoma (14). The results demonstrated that anlotinib significantly improved the median PFS compared with the placebo group (6.27 months vs. 1.47 months), along with higher ORR(10.13% vs. 1.33%) and DCR(55.7% vs. 22.67%). These outcomes are similar to the pooled results from the present meta-analysis, which showed a median PFS of 6.7 months (95% CI 5.7–7.6), an ORR of 9% (95% CI 5.4%–13.4%), and a DCR of 71.6% (95% CI 62.8%–79.6%).

Apatinib is a selective TKI that specifically targets VEGFR2 and demonstrates potent anti-tumor efficacy in a variety of malignancies. It suppresses tumor angiogenesis and induces autophagy and apoptosis in osteosarcoma cells by inhibiting the downstream VEGFR2/STAT3/BCL-2 signaling pathway (41). A retrospective study of apatinib in 105 patients with metastatic osteosarcoma refractory to standard chemotherapy demonstrated an ORR of 37.1%, a DCR of 77.1%, and a median PFS of 4.1 months (42). In a single-arm phase II study (NCT03121846) involving 42 patients with chemotherapy-resistant stage IV soft tissue sarcoma, treatment resulted in a median PFS of 7.9 months, an ORR of 23.7%, and a DCR of 57.9% (43). A meta-analysis was performed on 21 studies involving 827 patients with bone and soft tissue sarcoma who were treated with apatinib (44). The pooled ORR and DCR were 23.9% (95% CI: 18.5–30.2%) and 79.2% (95% CI: 73.8–83.7%), respectively. The median PFS reported across the included studies ranged from 3.5 to 13.1 months.

Regorafenib is an oral multikinase inhibitor targeting VEGFR1–3, c-KIT, RAF, and FGFR, which inhibits tumor angiogenesis and significantly delays tumor growth, and has been approved for treating metastatic colorectal cancer, advanced gastrointestinal stromal tumors, and hepatocellular carcinoma (45, 46). A randomized, double-blind phase II clinical trial of regorafenib for the treatment of advanced soft tissue sarcoma (REGOSARC, NCT01900743) enrolled 182 patients (47). The study population was stratified into four histological subtypes: liposarcoma, leiomyosarcoma synovial sarcoma, and other sarcomas. Results demonstrated that, compared with placebo, regorafenib significantly prolonged median PFS in all subgroups except the liposarcoma cohort. Notably, patients with synovial sarcoma derived the greatest benefit, achieving a median PFS of 5.6 months (95% CI: 1.4–11.6). DUFFAUD et al. (48) conducted a randomized, double-blind, placebo-controlled phase II trial (NCT02389244) of regorafenib in 43 patients with metastatic osteosarcoma. The study met its primary endpoint: 65.4% of patients receiving regorafenib were progression-free at 8 weeks versus 0% in the placebo group. Regorafenib treatment resulted in a median PFS of 4.1 months (95% CI, 2.0 to 6.8), with an ORR of 8% and a DCR of 65.4%. The 3- and 6-month PFS rates were 62% (95% CI, 40 to 77) and 35% (95% CI, 17 to 52), respectively. A meta-analysis involving 179 patients evaluated the safety and efficacy of regorafenib in the treatment of bone sarcoma (49). The results showed that regorafenib treatment was associated with significantly improved 3- and 6-month PFS rates in patients with metastatic or recurrent bone sarcomas compared to controls, with corresponding odds ratios of 2.04 (95% CI: 1.21–2.86; P < 0.01) and 1.03 (95% CI: 0.08–1.99; P < 0.05).

Pazopanib is an oral, selective TKI that targets VEGFR1-3, PDGFR, and c-KIT, resulting in significant inhibition of angiogenesis and tumor cell proliferation. It has been approved for the treatment of advanced renal cell carcinoma and soft tissue sarcoma (50, 51). In a retrospective analysis of 552 patients with metastatic sarcoma treated with pazopanib in Turkey, BILTIC et al. (52) reported that regardless of the line of therapy or histological subtype, the DCR and ORR were 43.1% and 30.8%, respectively. The median PFS was 6.7 months, and overall survival was 13.8 months.A separate retrospective study involving 123 patients evaluated the safety and efficacy of pazopanib in bone and soft tissue sarcomas (53). The results demonstrated a DCR of 46.3%, an ORR of 10.6%, and a median PFS of 3 months.

This meta-analysis included a total of 16 studies comprising 787 patients with bone or soft tissue sarcoma. The pooled ORR, DCR, and median PFS were 8.8% (95% CI: 6.2%–11.7%), 70.7% (95% CI: 64.8%–76.2%), and 6.68 months (95% CI: 5.37–7.98), respectively. In the soft tissue sarcoma subgroup, the ORR, DCR, and mPFS were 9.0% (95% CI: 5.4%–13.4%), 71.6% (95% CI: 62.8%–79.6%), and 6.7 months (95% CI: 5.7–7.6), respectively. Corresponding values in the bone sarcoma subgroup were 9.6% (95% CI: 4.5%–16.2%), 68.0% (95% CI: 50.0%–83.8%), and 5.7 months (95% CI: 1.2–10.3). These results indicate that anlotinib demonstrates comparable or superior clinical efficacy relative to apatinib, regorafenib, and pazopanib for treating these sarcomas. In terms of safety, treatment with anlotinib was associated with adverse events, which represented the most common reason for dose reduction or treatment discontinuation. The three most frequent adverse events were hand-foot syndrome (34.7%, 95% CI: 22.1%–48.3%), hypertension (32.4%, 95% CI: 21.8%–44%), and pharyngalgia (30.6%, 95% CI: 21.5%–40.4%). The incidence of grade ≥3 adverse events was relatively low; the most common included hypertension (7.9%, 95% CI: 4.7%–11.7%), hand-foot syndrome (2.9%; 95% CI: 1.1–5.4%), and pneumothorax (3.0%; 95% CI: 1.1–5.6%). However, all adverse events were manageable through dose interruption, dose reduction, and symptomatic treatment. The pooled safety profile observed in this study is consistent with that of other targeted agents used in the treatment of bone and soft tissue sarcomas. Furthermore, these findings align with previous experience with anlotinib in other refractory solid tumors, including non-small cell lung cancer, thyroid carcinoma, and digestive system neoplasms (54–56).

Finally, we acknowledge that there were several limitations in the present meta-analysis. First, considerable heterogeneity was observed among the included studies. Although subgroup analyses were performed between bone and soft tissue sarcomas, significant heterogeneity persisted across different histological subtypes. Further investigations are warranted to evaluate the efficacy of anlotinib in specific sarcoma subtypes. Second, all incorporated studies were non-randomized and lacked control groups, which inherently lowers the level of evidence and may influence the overall validity of the findings. Moreover, the current analysis assessed only efficacy and safety outcomes without yielding definitive conclusions. Third, this analysis was restricted to studies of anlotinib monotherapy, whereas combination regimens (e.g., with chemotherapy or immunotherapy) are more prevalent in clinical practice. The efficacy and safety of such combinations require further exploration. Fourth, all studies included in this meta-analysis were conducted in Chinese populations with a relatively limited sample size. Whether these findings can be generalized to other ethnic populations remains uncertain. Therefore, large-scale, multicenter, randomized controlled trials are needed to validate the clinical role of anlotinib in comparison to other agents and in diverse patient populations.

Conclusion

In summary, this meta-analysis demonstrates the efficacy and safety of anlotinib in patients with bone and soft tissue sarcomas, thereby providing evidence to support its clinical application. Treatment with anlotinib was associated with favorable ORR, DCR, PFS, and OS. Although treatment-related adverse events were common, the majority were grade 1–2 and proved largely manageable with appropriate clinical interventions. Therefore, anlotinib is a viable option in both the first- and second-line settings for sarcoma patients. It can be considered for first-line use in patients ineligible for standard chemotherapy, and it is an important option following the failure of prior chemotherapy. Nonetheless, due to the limitations inherent in the included studies, further high-quality clinical trials are required to more definitively establish its activity and toxicity profile within specific single subtype sarcoma.

The progression of precision medicine is shifting cancer treatment toward personalization. Consequently, future clinical trial designs will depend less on histologic subtype and more on specific molecular genetic alterations. This is essential for optimizing targeted therapy in the highly heterogeneous sarcoma family. Furthermore, the limitations of monotherapies have driven the development of combination strategies. Among these, the combination of targeted agents with immune checkpoint inhibitors demonstrates promising synergistic efficacy. A primary objective of next-stage clinical research will be to identify the optimal combination regimens, dosing sequences, and biomarkers for predicting response. Additionally, combining targeted therapy with chemotherapy, radiotherapy, or epigenetic drugs also warrants extensive investigation.

Data availability statement

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

Author contributions

ZL: Conceptualization, Data curation, Formal analysis, Software, Writing – original draft, Writing – review & editing. PF: Conceptualization, Data curation, Formal analysis, Software, Writing – original draft, Writing – review & editing. SS: Conceptualization, Data curation, Formal analysis, Software, Writing – review & editing. LZ: Conceptualization, Data curation, Formal analysis, Software, Supervision, Writing – review & editing. RX: Conceptualization, Data curation, Formal analysis, Supervision, Writing – review & editing, Software. CL: Conceptualization, Data curation, Formal analysis, Funding acquisition, Resources, Supervision, Writing – review & editing, Investigation, Methodology, Project administration, Software, Validation, Visualization.

Funding

The author(s) declare that no financial support was received for the research, and/or publication of this article.

Conflict of interest

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.

Generative AI statement

The author(s) declare that no Generative AI was used in the creation of this manuscript.

Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

References

1. Burningham Z, Hashibe M, Spector L, and Schiffman JD. The epidemiology of sarcoma. Clin sarcoma Res. (2012) 2:14. doi: 10.1186/2045-3329-2-14

PubMed Abstract | Crossref Full Text | Google Scholar

2. Anderson WJ and Doyle LA. Updates from the 2020 world health organization classification of soft tissue and bone tumours. Histopathology. (2021) 78:644–57. doi: 10.1111/his.14265

PubMed Abstract | Crossref Full Text | Google Scholar

3. Ritter J and Bielack SS. Osteosarcoma. Ann Oncol. (2010) 21:vii320-5. doi: 10.1093/annonc/mdq276

PubMed Abstract | Crossref Full Text | Google Scholar

4. Spalato-Ceruso M, Ghazzi NE, and Italiano A. New strategies in soft tissue sarcoma treatment. J Hematol Oncol. (2024) 17:76. doi: 10.1186/s13045-024-01580-3

PubMed Abstract | Crossref Full Text | Google Scholar

5. Judson I, Verweij J, Gelderblom H, Hartmann JT, Schöffski P, Blay JY, et al. Doxorubicin alone versus intensified doxorubicin plus ifosfamide for first-line treatment of advanced or metastatic soft-tissue sarcoma: a randomised controlled phase 3 trial. Lancet Oncol. (2014) 15:415–23. doi: 10.1016/s1470-2045(14)70063-4

PubMed Abstract | Crossref Full Text | Google Scholar

6. Saerens M, Brusselaers N, Rottey S, Decruyenaere A, Creytens D, and Lapeire L. Immune checkpoint inhibitors in treatment of soft-tissue sarcoma: A systematic review and meta-analysis. Eur J Cancer (Oxford England: 1990). (2021) 152:165–82. doi: 10.1016/j.ejca.2021.04.034

PubMed Abstract | Crossref Full Text | Google Scholar

7. Ghignatti P, Nogueira LJ, Lehnen AM, and Leguisamo NM. Cardioprotective effects of exercise training on doxorubicin-induced cardiomyopathy: a systematic review with meta-analysis of preclinical studies. Sci Rep. (2021) 11:6330. doi: 10.1038/s41598-021-83877-8

PubMed Abstract | Crossref Full Text | Google Scholar

8. Folkman J. Role of angiogenesis in tumor growth and metastasis. Semin Oncol. (2002) 29:15–8. doi: 10.1053/sonc.2002.37263

PubMed Abstract | Crossref Full Text | Google Scholar

9. Khan JA, Maki RG, and Ravi V. Pathologic angiogenesis of Malignant vascular sarcomas: implications for treatment. J Clin Oncol. (2018) 36:194–201. doi: 10.1200/jco.2017.74.9812

PubMed Abstract | Crossref Full Text | Google Scholar

10. English WR, Lunt SJ, Fisher M, Lefley DV, Dhingra M, Lee Y-C, et al. Differential expression of VEGFA isoforms regulates metastasis and response to anti-VEGFA therapy in sarcoma. Cancer Res. (2017) 77:2633–46. doi: 10.1158/0008-5472.CAN-16-0255

PubMed Abstract | Crossref Full Text | Google Scholar

11. Wesche J, Haglund K, and Haugsten EM. Fibroblast growth factors and their receptors in cancer. Biochem J. (2011) 437:199–213. doi: 10.1042/bj20101603

PubMed Abstract | Crossref Full Text | Google Scholar

12. Ehnman M, Missiaglia E, Folestad E, Selfe J, Strell C, Thway K, et al. Distinct effects of ligand-induced PDGFRα and PDGFRβ signaling in the human rhabdomyosarcoma tumor cell and stroma cell compartments. Cancer Res. (2013) 73:2139–49. doi: 10.1158/0008-5472.Can-12-1646

PubMed Abstract | Crossref Full Text | Google Scholar

13. Shen G, Zheng F, Ren D, Du F, Dong Q, Wang Z, et al. Anlotinib: a novel multi-targeting tyrosine kinase inhibitor in clinical development. J Hematol Oncol. (2018) 11:120. doi: 10.1186/s13045-018-0664-7

PubMed Abstract | Crossref Full Text | Google Scholar

14. Chi Y, Yao Y, Wang S, Huang G, Cai Q, Shang G, et al. Anlotinib for metastasis soft tissue sarcoma: A randomized, double-blind, placebo-controlled and multi-centered clinical trial. J Clin Oncol. (2018) 36:11503. doi: 10.1200/JCO.2018.36.15_suppl.11503

Crossref Full Text | Google Scholar

15. Han B, Li K, Wang Q, Zhang L, Shi J, Wang Z, et al. Effect of anlotinib as a third-line or further treatment on overall survival of patients with advanced non-small cell lung cancer: the ALTER 0303 phase 3 randomized clinical trial. JAMA Oncol. (2018) 4:1569–75. doi: 10.1001/jamaoncol.2018.3039

PubMed Abstract | Crossref Full Text | Google Scholar

16. Li D, Chi Y, Chen X, Ge M, Zhang Y, Guo Z, et al. Anlotinib in locally advanced or metastatic medullary thyroid carcinoma: A randomized, double-blind phase IIB trial. Clin Cancer Res. (2021) 27:3567–75. doi: 10.1158/1078-0432.Ccr-20-2950

PubMed Abstract | Crossref Full Text | Google Scholar

17. Slim K, Nini E, Forestier D, Kwiatkowski F, Panis Y, and Chipponi J. Methodological index for non-randomized studies (minors): development and validation of a new instrument. ANZ J surg. (2003) 73:712–6. doi: 10.1046/j.1445-2197.2003.02748.x

PubMed Abstract | Crossref Full Text | Google Scholar

18. Munn Z, Barker TH, Moola S, Tufanaru C, Stern C, McArthur A, et al. Methodological quality of case series studies: an introduction to the JBI critical appraisal tool. JBI evidence synthesis. (2020) 18:2127–33. doi: 10.11124/jbisrir-d-19-00099

PubMed Abstract | Crossref Full Text | Google Scholar

19. Nyaga VN, Arbyn M, and Aerts M. Metaprop: a Stata command to perform meta-analysis of binomial data. Arch Public Health = Arch belges sante publique. (2014) 72:39. doi: 10.1186/2049-3258-72-39

PubMed Abstract | Crossref Full Text | Google Scholar

20. Chi Y, Fang Z, Hong X, Yao Y, Sun P, Wang G, et al. Safety and efficacy of anlotinib, a multikinase angiogenesis inhibitor, in patients with refractory metastatic soft-tissue sarcoma. Clin Cancer Res. (2018) 24:5233–8. doi: 10.1158/1078-0432.CCR-17-3766

PubMed Abstract | Crossref Full Text | Google Scholar

21. Li T, Dong Y, Wei Y, Wang S, Liu Y, Chen J, et al. First-line anlotinib treatment for soft-tissue sarcoma in chemotherapy-ineligible patients: an open-label, single- arm, phase 2 clinical trial. Clin Cancer Res. (2024) 30:4310–7. doi: 10.1158/1078-0432.CCR-23-3983

PubMed Abstract | Crossref Full Text | Google Scholar

22. Liu J, Fan Z, Li S, Xue R, Gao T, Bai C, et al. Anlotinib hydrochloride capsules for advanced soft tissue sarcoma: Single-center data analysis of a stage II multicenter clinical trial. Chin J Clin Oncol. (2018) 45:1066–70. doi: 10.3969/j.issn.1000-8179.2018.20.632

Crossref Full Text | Google Scholar

23. Xu B, Pan Q, Pan H, Li H, Li X, Chen J, et al. Anlotinib as a maintenance treatment for advanced soft tissue sarcoma after first-line chemotherapy (ALTER-S006): a multicentre, open-label, single-arm, phase 2 trial. eClinicalMedicine. (2023) 64:102240. doi: 10.1016/j.eclinm.2023.102240

PubMed Abstract | Crossref Full Text | Google Scholar

24. Tang L, Niu X, Wang Z, Cai Q, Tu C, Fan Z, et al. Anlotinib for recurrent or metastatic primary Malignant bone tumor: A multicenter, single-arm trial. Front Oncol. (2022) 12:811687. doi: 10.3389/fonc.2022.811687

PubMed Abstract | Crossref Full Text | Google Scholar

25. Lu S, Que Y, Liu D, Sun F, Yao X, Deng L, et al. Safety and feasibility of anlotinib in children with high risk, recurrent or refractory sarcomas: an open-label, single-centre, single-arm, phase Ia/Ib trial. eClinicalMedicine. (2025) 84:103258. doi: 10.1016/j.eclinm.2025.103258

PubMed Abstract | Crossref Full Text | Google Scholar

26. Zheng A, Liu J, Liu Z, Mo Z, Fu Y, Deng Y, et al. Efficacies of anlotinib monotherapy versus gemcitabine-based chemotherapy for patients with advanced soft tissue sarcoma after the failure of anthracycline-based chemotherapy. J Cancer Res Clin Oncol. (2024) 150:58. doi: 10.1007/s00432-023-05575-4

PubMed Abstract | Crossref Full Text | Google Scholar

27. Liu Z, Gao S, Zhu L, Wang J, Zhang P, Li P, et al. Efficacy and safety of anlotinib in patients with unresectable or metastatic bone sarcoma: A retrospective multiple institution study. Cancer Med. (2021) 10:7593–600. doi: 10.1002/cam4.4286

PubMed Abstract | Crossref Full Text | Google Scholar

28. Pang L, Zhang S, Zhang X, Wang L, and He W. Safety and efficacy of anlotinib in patients with unresectable or metastatic bone and soft-tissue sarcomas: a retrospective institution study. Tumor. (2023) 43:710–9. doi: 10.3781/j.issn.1000-7431.2023.2302-0085

Crossref Full Text | Google Scholar

29. Qiang Y, Weitao Y, Xinhui D, Liangyu G, and Yichao F. Efficacy and safety of Anlotinib in the treatment of advanced sarcoma. Chin J Oncol. (2023) 45:904–10. doi: 10.3760/cma.j.cn112152-20210820-00632

PubMed Abstract | Crossref Full Text | Google Scholar

30. Liu J, Deng YT, and Jiang Y. Switch maintenance therapy with anlotinib after chemotherapy in unresectable or metastatic soft tissue sarcoma: a single-center retrospective study. Investigational New Drugs. (2021) 39:330–6. doi: 10.1007/s10637-020-01015-z

PubMed Abstract | Crossref Full Text | Google Scholar

31. Li Z-K, Liu J, Deng Y-T, and Jiang Y. Efficacy and safety of anlotinib in patients with unresectable or metastatic well-differentiated/dedifferentiated liposarcoma: a single-center retrospective study. Anti-Cancer Drugs. (2021) 32:210–4. doi: 10.1097/cad.0000000000001023

PubMed Abstract | Crossref Full Text | Google Scholar

32. Zhang X-Y, Liu J, Deng Y-T, and Jiang Y. Anlotinib treatment in elderly patients with unresectable or metastatic soft tissue sarcoma: a retrospective study. Anti-Cancer Drugs. (2022) 33:E519–E24. doi: 10.1097/cad.0000000000001154

PubMed Abstract | Crossref Full Text | Google Scholar

33. Li H, Li Y, Song L, Ai Q, and Zhang S. Retrospective review of safety and efficacy of anlotinib in advanced osteosarcoma with metastases after failure of standard multimodal therapy. Asia Pac J Clin Oncol. (2023) 19:e314–e9. doi: 10.1111/ajco.13916

PubMed Abstract | Crossref Full Text | Google Scholar

34. Gan HZ. (2022)., in: Clinical application of anlotinib in the treatment of advanced bone and soft tissue sarcoma. Kunming: Kunming Medical University. doi: 10.27202/d.cnki.gkmyc.2022.000392

Crossref Full Text | Google Scholar

35. Tian Z, Liu H, Zhang F, Li L, Du X, Li C, et al. Retrospective review of the activity and safety of apatinib and anlotinib in patients with advanced osteosarcoma and soft tissue sarcoma. Invest New Drugs. (2020) 38:1559–69. doi: 10.1007/s10637-020-00912-7

PubMed Abstract | Crossref Full Text | Google Scholar

36. Gaspar N, Campbell-Hewson Q, Gallego Melcon S, Locatelli F, Venkatramani R, Hecker-Nolting S, et al. Phase I/II study of single-agent lenvatinib in children and adolescents with refractory or relapsed solid Malignancies and young adults with osteosarcoma (ITCC-050)(☆). ESMO Open. (2021) 6:100250. doi: 10.1016/j.esmoop.2021.100250

PubMed Abstract | Crossref Full Text | Google Scholar

37. Xie L, Ji T, and Guo W. Anti-angiogenesis target therapy for advanced osteosarcoma (Review). Oncol Rep. (2017) 38:625–36. doi: 10.3892/or.2017.5735

PubMed Abstract | Crossref Full Text | Google Scholar

38. Hayashi T, Horiuchi A, Sano K, Kanai Y, Yaegashi N, Aburatani H, et al. Biological characterization of soft tissue sarcomas. Ann Transl Med. (2015) 3:368. doi: 10.3978/j.issn.2305-5839.2015.12.33

PubMed Abstract | Crossref Full Text | Google Scholar

39. Smolle MA, Szkandera J, Andreou D, Palmerini E, Bergovec M, and Leithner A. Treatment options in unresectable soft tissue and bone sarcoma of the extremities and pelvis - a systematic literature review. EFORT Open Rev. (2020) 5:799–814. doi: 10.1302/2058-5241.5.200069

PubMed Abstract | Crossref Full Text | Google Scholar

40. Sun Y, Niu W, Du F, Du C, Li S, Wang J, et al. Safety, pharmacokinetics, and antitumor properties of anlotinib, an oral multi-target tyrosine kinase inhibitor, in patients with advanced refractory solid tumors. J Hematol Oncol. (2016) 9:105. doi: 10.1186/s13045-016-0332-8

PubMed Abstract | Crossref Full Text | Google Scholar

41. Han G, Guo Q, Ma N, Bi W, Xu M, and Jia J. Apatinib inhibits cell proliferation and migration of osteosarcoma via activating LINC00261/miR-620/PTEN axis. Cell Cycle (Georgetown Tex). (2021) 20:1785–98. doi: 10.1080/15384101.2021.1949132

PubMed Abstract | Crossref Full Text | Google Scholar

42. Liu J-Y, Zhu B-R, Wang Y-D, and Sun X. The efficacy and safety of Apatinib mesylate in the treatment of metastatic osteosarcoma patients who progressed after standard therapy and the VEGFR2 gene polymorphism analysis. Int J Clin Oncol. (2020) 25:1195–205. doi: 10.1007/s10147-020-01644-7

PubMed Abstract | Crossref Full Text | Google Scholar

43. Liu X, Xu J, Li F, Liao Z, Ren Z, Zhu L, et al. Efficacy and safety of the VEGFR2 inhibitor Apatinib for metastatic soft tissue sarcoma: Chinese cohort data from NCT03121846. Biomed Pharmacother. (2019) 122:109587. doi: 10.1016/j.biopha.2019.109587

PubMed Abstract | Crossref Full Text | Google Scholar

44. Long Z, Huang M, Liu K, Li M, Li J, Zhang H, et al. Assessment of efficiency and safety of apatinib in advanced bone and soft tissue sarcomas: A systematic review and meta-analysis. Front Oncol. (2021) 11:662318. doi: 10.3389/fonc.2021.662318

PubMed Abstract | Crossref Full Text | Google Scholar

45. Casanova M, Bautista F, Campbell-Hewson Q, Makin G, Marshall LV, Verschuur AC, et al. Regorafenib plus vincristine and irinotecan in pediatric patients with recurrent/refractory solid tumors: an innovative therapy for children with cancer study. Clin Cancer Res. (2023) 29:4341–51. doi: 10.1158/1078-0432.Ccr-23-0257

PubMed Abstract | Crossref Full Text | Google Scholar

46. Wilhelm SM, Dumas J, Adnane L, Lynch M, Carter CA, Schütz G, et al. Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity. Int J Cancer. (2011) 129:245–55. doi: 10.1002/ijc.25864

PubMed Abstract | Crossref Full Text | Google Scholar

47. Mir O, Brodowicz T, Italiano A, Wallet J, Blay JY, Bertucci F, et al. Safety and efficacy of regorafenib in patients with advanced soft tissue sarcoma (REGOSARC): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. (2016) 17:1732–42. doi: 10.1016/s1470-2045(16)30507-1

PubMed Abstract | Crossref Full Text | Google Scholar

48. Duffaud F, Mir O, Boudou-Rouquette P, Piperno-Neumann S, Penel N, Bompas E, et al. Efficacy and safety of regorafenib in adult patients with metastatic osteosarcoma: a non-comparative, randomised, double-blind, placebo-controlled, phase 2 study. Lancet Oncol. (2019) 20:120–33. doi: 10.1016/s1470-2045(18)30742-3

PubMed Abstract | Crossref Full Text | Google Scholar

49. Han Y, Xie J, Wang Y, Liang X, and Xie Y. Efficacy and safety of regorafenib in the treatment of bone sarcomas: systematic review and meta-analysis. BMC Cancer. (2025) 25:302. doi: 10.1186/s12885-025-13722-y

PubMed Abstract | Crossref Full Text | Google Scholar

50. Lee ATJ, Jones RL, and Huang PH. Pazopanib in advanced soft tissue sarcomas. Signal transduction targeted Ther. (2019) 4:16. doi: 10.1038/s41392-019-0049-6

PubMed Abstract | Crossref Full Text | Google Scholar

51. Manz KM, Fenchel K, Eilers A, Morgan J, Wittling K, and Dempke WCM. Efficacy and safety of approved first-line tyrosine kinase inhibitor treatments in metastatic renal cell carcinoma: A network meta-analysis. Adv Ther. (2020) 37:730–44. doi: 10.1007/s12325-019-01167-2

PubMed Abstract | Crossref Full Text | Google Scholar

52. Bilici A, Koca S, Karaagac M, Aydin SG, Eraslan E, Kaplan MA, et al. Real-world outcomes of pazopanib in metastatic soft tissue sarcoma: a retrospective Turkish oncology group (TOG) study. J Cancer Res Clin Oncol. (2023) 149:8243–53. doi: 10.1007/s00432-023-04766-3

PubMed Abstract | Crossref Full Text | Google Scholar

53. Seto T, Song MN, Trieu M, Yu J, Sidhu M, Liu CM, et al. Real-world experiences with pazopanib in patients with advanced soft tissue and bone sarcoma in northern California. Med Sci (Basel Switzerland). (2019) 7:48. doi: 10.3390/medsci7030048

PubMed Abstract | Crossref Full Text | Google Scholar

54. Yu G, Shen Y, Xu X, and Zhong F. Anlotinib for refractory advanced non-small-cell lung cancer: A systematic review and meta-analysis. PLoS One. (2020) 15:e0242982. doi: 10.1371/journal.pone.0242982

PubMed Abstract | Crossref Full Text | Google Scholar

55. Kuang B-H, Zhang W-X, Lin G-H, Fu C, Cao R-B, and Wang B-C. Tyrosine kinase inhibitors in patients with advanced anaplastic thyroid cancer: an effective analysis based on real-world retrospective studies. Front Endocrinol (Lausanne) (2024) 15:1345203. doi: 10.3389/fendo.2024.1345203

PubMed Abstract | Crossref Full Text | Google Scholar

56. Zhou C, Wang W, Mu Y, and Meng M. Efficacy and safety of a novel TKI (anlotinib) for the treatment of advanced digestive system neoplasms: a systematic review and meta-analysis. Front Immunol. (2024) 15:1393404. doi: 10.3389/fimmu.2024.1393404

PubMed Abstract | Crossref Full Text | Google Scholar