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. 2024 Mar 15;103(11):e37423. doi: 10.1097/MD.0000000000037423

Efficacy of tyrosine kinase inhibitors in patients with advanced or metastatic sarcomas after prior chemotherapy: A meta-analysis

Wenxia Li a, Liwen Liu a, Zhanpeng Liang a, Huiqin Lai a, Jiaming Wu a, Huatang Zhang a, Cantu Fang a,*
PMCID: PMC10939701  PMID: 38489731

Abstract

Background:

Sarcoma is a heterogeneous malignancy arising from interstitial tissue. Anthracycline-based therapy is the first-line treatment recommended by guidelines for patients with locally advanced or metastatic unresectable sarcoma. Recently, targeted therapies, in particular tyrosine kinase inhibitors (TKIs), have made significant progress in the treatment of sarcoma, and their efficacy has been investigated in randomized controlled trials. The aim of this meta-analysis is to evaluate the efficacy of TKIs in patients with advanced or metastatic sarcoma who have previously received chemotherapy.

Methods:

We completed a meta-analysis after conducting literature searches in PubMed, Embase, and Cochrane. The single-drug, placebo-controlled, randomized controlled clinical trials of TKIs in patients with advanced or progressive sarcoma who have previously received chemotherapy are available for inclusion in the study. The observation results were objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). The subgroup analysis was performed according to histological subtypes of sarcoma.

Results:

This study included 6 studies, including 1033 patients. The ORR (OR: 7.99, 95% CI: 3.62–19.61, P < .00001), DCR (OR: 2.54, 95% CI: 1.27–5.08, P = .009), PFS (HR: 0.46, 95% CI: 0.34–0.62, P < .00001), and OS (HR: 0.80, 95% CI: 0.67–0.96, P = .02) of patients treated with TKIs were better than those in the placebo group.

Conclusions:

In patients with advanced sarcoma, TKIs have been shown to have advantages in terms of ORR, DCR and PFS and OS. Multi-targeted TKIs may be considered as one of the second-line treatment options for sarcoma patients who have received prior chemotherapy.

Keywords: meta-analysis, prior chemotherapy, sarcoma, soft tissue sarcoma, tyrosine kinase inhibitors

1. Introduction

Sarcoma is a highly heterogeneous malignant neoplasms originating from interstitial tissue. Although sarcoma is rare in adult malignancies, accounting for about 1% of all adult malignancies,[1] they account for 12% to 15% of all pediatric tumors.[2,3] Sarcoma are often divided into bone sarcoma and soft tissue sarcoma (STS), depending on where they occur. The most common histological types of STS are liposarcoma and leiomyosarcoma. And Osteosarcoma and chondrosarcoma are more common in bone sarcoma.

Surgery and radiotherapy are still the main treatments for localized sarcomas. The use of postoperative adjuvant therapy, whether chemotherapy or radiotherapy, is controversial. Adjuvant chemotherapy may be a viable option for patients with high-risk early and metastatic STS (high-grade, deep, >5 cm tumors). Postoperative adjuvant hormonal therapy may have potential benefits in the management of uterine sarcomas, although its efficacy is still controversial. It is recommended for patients with strongly positive hormone receptor expression.[4] For patients with locally advanced unresectable sarcoma, anthracycline-based treatment is the first-line treatment recommended by guidelines [I, A].[5–7] Anthracyclines and isocyclophosphamide represent the foundation of chemotherapy for STS. The median progression-free survival (PFS) of first-line chemotherapy is approximately 4–6 months, and the overall survival (OS) is about 12 to 27 months.[6] Patients with advanced sarcoma generally have a bleak prognosis. For patients with metastatic disease or recurrence, survival for more than 3 years is uncommon, with <20% of patients achieving this milestone.[8] The optimal second-line treatment regimen for STS has not yet been determined. Eribulin, Trabectedin, temozolomide, and dacarbazine have shown efficacy in the second-line chemotherapy of STS. It is important to consider the histologic type of the tumor, the sensitivity of the tumor to chemotherapy, and the history of previous treatment in the determination of the chemotherapy regimen for the treatment of STS.

Due to the heterogeneity of sarcomas and the absence of gene-driven mutations, there is a comparative lack of research on targeted therapies. Research into sarcoma genomics and mutations in signaling pathways has led to the development of targeted therapies for sarcomas. Significant progress has been made in the treatment of sarcoma with tyrosine kinase inhibitors (TKIs), particularly those targeting angiogenesis. Tyrosine kinases (TKs) play a crucial role in signal transduction and the regulation of cell cycle, mitosis, proliferation, differentiation, adhesion, migration, and apoptosis.[9] Other evidence suggests that TKIs may have anti-tumor activity in the treatment of sarcoma through inhibition of VEGFR-mediated angiogenesis and RTK-mediated cell growth.[10–13]

TKIs has provided significant benefit for some STS. Imatinib has been shown to improve recurrence-free survival after surgical resection of gastrointestinal stromal tumors (GIST) as an adjuvant treatment option.[14] It has also been shown to be effective in the neoadjuvant treatment of advanced or recurrent dermatofibrosarcoma protuberans.[15] However, there is currently no widely accepted treatment option for patients with advanced unspecified STS who are unsuitable for chemotherapy. The ALTER-S003[16] study (NCT03792542) demonstrated the promising activity of anlotinib as a first-line treatment option for patients with advanced STS who are unsuitable for chemotherapy. In addition, pazopanib has become one of the recommended treatment options for non-liposarcoma.[17] In addition, other small molecule TKIs targeting angiogenesis, including sunitinib, sorafenib, regorafenib, cediranib, and apatinib, have demonstrated activity in leiomyosarcoma, synovial sarcoma (SS), alveolar soft part sarcoma (ASPS), isolated fibrous tumors and hemangiosarcoma. The effectiveness of immune checkpoint inhibitors in treating sarcoma has garnered considerable attention. In the phase II SARC-028 study (NCT02301039), Pembrolizumab showed encouraging activity in patients with undifferentiated pleomorphic sarcoma or dedifferentiated liposarcoma.[18] Furthermore, pembrolizumab has been shown to be effective in treating ASPS.[19,20] A meta-analysis evaluating immune checkpoint inhibitors for the treatment of STS showed that immune checkpoint inhibitors were effective in classic Kaposi sarcoma, ASPS and undifferentiated pleomorphic sarcoma.[21]

Currently, the optimal second-line treatment for sarcoma remains unclear. Therefore, it is imperative to identify effective treatments for locally advanced or metastatic sarcoma.[6] Pazopanib, anlotinib, and regorafenib are viable second-line treatment options for patients with unresectable or advanced STS. In addition, numerous clinical trials have evaluated the efficacy of TKIs as a second-line treatment option after chemotherapy in advanced unresectable and metastatic sarcomas. Our meta-analysis aimed to evaluate the efficacy of TKIs in patients with the most common subtypes of advanced sarcomas who have received prior chemotherapy.

2. Methods

This study was registered in the PROSPERO database (CRD42023405397) and was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.[22] The objective of this study is to compare the efficacy of TKIs in patients with advanced or metastatic sarcoma after having received prior chemotherapy.

2.1. Search strategy

We did a systematic search for trials in PubMed, Embase and Cochrane. The corresponding keywords or terms used to search were “sarcoma,” “tyrosine kinase inhibitors,” “TKIs,” “soft tissue sarcoma,” “STS,” and “bone sarcoma.” A full electronic search strategy is described in the eMethod 1 in the Supplemental Content, http://links.lww.com/MD/L920. All publications are in English language. Reference lists of studies selected through electronic searches were manually retrieved to identify other relevant studies. The most complete and recent report was selected for inclusion in this meta-analysis when data overlapped. The date of the last literature search was February 15, 2023.

2.2. Eligibility criteria

The inclusion criteria used to select studies for this meta-analysis were: Randomized controlled trials evaluating the efficacy of TKIs in patients with sarcoma who had received prior chemotherapy. Patients with histologically proven advanced and inoperable sarcoma. Phase II or III randomized, controlled clinical trials comparing TKI monotherapy with placebo. Trials reporting at least one of the following endpoints: objective response rate (ORR), disease control rate (DCR), PFS, and OS.

The following exclusion criteria were applied: Studies that investigated the combination of TKIs with other therapies. Non-randomized controlled trials, fundamental research, retrospective studies, case reports, duplicate publications, and studies for which relevant data are not available.

2.3. Study selection and data extraction

Two researchers conducted studies selection and data extraction independently, and any discrepancies were resolved through discussion with a third researcher. After retrieving references from electronic databases, duplicate articles were removed using literature management software. Potentially eligible literatures were subsequently screened by scanning titles and abstracts. Finally, the full texts of the potentially eligible literature were reviewed to determine its eligibility. When overlapping patients were included in different articles, we preferred to extract outcome data from the primary article with the largest sample size for early outcomes and the article with the longest follow-up for late outcomes. The extracted data included baseline characteristics, sample size, treatment regimen, and histologic typing for each patient. The analysis aimed to evaluate the ORR, DCR, PFS, and OS.

2.4. Quality assessment

The Cochrane Bias Risk Tool was used to conduct a risk assessment for bias in each trial. The assessment evaluated 7 areas related to treatment effectiveness bias, including random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome evaluations, incomplete outcome data, selective reporting, and other biases.[23] The quality of the trials was assessed independently by 2 authors, and differences were resolved by discussion with a third reviewer.

2.5. Statistical analysis

All statistical analyses were conducted using Review Manager 5.4 software. The Q-test and I2 statistics were used to evaluate heterogeneity among included studies. If there was significant heterogeneity between studies (I2 > 50%), a random-effects model was used; otherwise, a fixed-effects model was used. The overall analysis of OS and PFS was performed using the inverse variance method and expressed as hazard ratio (HR) and 95% confidence interval (CI). ORR and DCR were comprehensively analyzed using the M-H method and expressed by odds ratio (OR) and 95% CI.[24,25] In addition, the publication bias of selected studies was assessed using the Egger regression test and funnel plot.[26] Two-sided P < .05 was considered statistically significant.

3. Results

3.1. Study identification and quality assessment

A total of 1571 articles were retrieved from 3 electronic databases: PubMed, Embase, and the Cochrane Library. All search results were filtered and selected using Endnote. The flowchart describing the process of identifying and selecting studies is shown in eFigure 1 in the Supplemental Content, http://links.lww.com/MD/L912. After removing 125 repetitive articles, 1446 articles were identified by reading and screening the title and abstract. 1431 articles were excluded from the study. The majority of these excluded references were non-clinical studies (including reviews, pathological reports, in vitro studies, retrospective studies, and meta-analyses), lack of relevance to the topic of the analysis (TKIs in combination with other therapies, patients who had not previously received chemotherapy, and patients with non-advanced or non-metastatic sarcoma), and non-randomized studies. After reading the full text, 8 of the remaining 16 articles were excluded. The reasons for exclusion were non-monotherapy with TKIs (n = 1), non-placebo control (n = 1), patients with advanced sarcoma who had not previously received chemotherapy (n = 3), lack of sufficient research data (n = 2), and duplicated literature (n = 1).

3.2. Study and patient characteristics

Six randomized controlled trials were eventually included: REGOSARC,[27,28] SARC024,[29,30] PALETTE,[17] CASPS,[31] ALTER0203,[32] and REGOBONE.[33,34] The characteristics of these trials are listed in eTable 1 in the Supplemental Content, http://links.lww.com/MD/L913. As shown in eFigure 2 and 3 in the Supplemental Content; http://links.lww.com/MD/L914; http://links.lww.com/MD/L915, the overall risk of bias assessment for the included randomized trials is low.

REGOSARC was a Phase II study conducted in France and Austria from August 5, 2013 to November 26, 2014. It was a double-blind, placebo-controlled, multicenter, randomized trial that enrolled 182 patients aged 18 years or older with advanced STS who had previously received doxorubicin or other anthracycline-based regimens. Patients were randomly assigned (1:1) to 1 of 4 cohorts: liposarcomas, leiomyosarcomas, SS and other sarcomas. Patients in the placebo group were permitted to cross over as disease progressed. Additionally, 37 patients diagnosed with metastatic non-adipocytic STS who had previously received chemotherapy in combination with pazopanib were enrolled in REGOSARC.

The Phase II clinical trial SARC024 evaluated the efficacy of regorafenib in specific sarcoma subtypes, including osteosarcoma and liposarcoma cohorts. Patients who had previously received small molecule TKIs were excluded. A total of 42 patients with osteosarcoma were enrolled, of which 20 patients were assigned to the placebo group and 10 of these patients were crossed over to regorafenib treatment due to disease progression. In the liposarcoma cohort, 48 patients were randomly assigned (1:1) to regorafenib and placebo. Crossover was allowed as the disease progressed in the placebo group.

PALETTE was a randomized, double-blind, placebo-controlled Phase 3 trial of pazopanib for the treatment of metastatic STS. The study enrolled 369 patients who had previously received chemotherapy and had disease progression, except for patients with gastrointestinal stromal tumors and liposarcoma. There was no subsequent crossover for the patients.

CASPS was a double-blind, placebo-controlled, randomized Phase 2 study of cediranib for the treatment of ASPS. From July 15, 2011, to July 29, 2016, 48 participants were randomized to receive cediranib (n = 32) or placebo (n = 16). After 24 weeks of disease progression or observation, patients in the placebo arm may cross over to cediranib treatment. The primary outcome measure was the percentage change in the sum of target marker lesion diameters from randomization to week 24. At the same time, this clinical trial also provides the results of PFS.

ALTER0203 evaluated the efficacy of anlotinib in patients with advanced STS after the failure of standard chemotherapy. The final analysis included 233 patients who were randomly assigned to receive either anlotinib (n = 158) or placebo (n = 75). The pathological subtypes included SS, ASPS, and leiomyosarcoma.

REGOBONE was a phase 2 study that evaluated the efficacy of regorafenib in treating patients with metastatic bone sarcoma. The study was non-comparative, randomized, double-blind, and placebo-controlled. The study included 5 cohorts, including osteosarcoma and chondrosarcoma, with a total of 43 osteosarcoma and 40 chondrosarcoma patients recruited. The placebo group was allowed to crossover to regorafenib treatment after disease progression or after observation.

Except for the REGOSARC non-liposarcoma cohort, which specifically includes patients who have received prior chemotherapy plus pazopanib, all other cohorts are advanced sarcoma patients who have received prior chemotherapy. Patients in the placebo arm were allowed to switch to TKIs in all trials except PALETTE. Although the primary outcomes of the various clinical trials differ, they provide data related to either PFS or OS.

3.3. Results of meta-analysis

3.3.1. Objective response rate.

A total of 911 patients were included in this analysis. The analysis revealed the the ORR of patients treated with TKIs was was significantly improved compared to placebo (OR: 7.99, 95% CI: 3.62–19.61; P < .0001). No significant heterogeneity was found in studies of ORR analysis (Chi2 = 6.33, df = 6 [P = .39]; I2 = 5%, Figure 1).

Figure 1.

Figure 1.

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Assessment of Objective Response Rate (ORR). The diamond indicates best estimate of the true (pooled) outcome (with width indicating 95% CI); experimental stands for tyrosine kinase inhibitors (TKIs); control stands for placebo. Since there is a low heterogeneity, a fixed-effects model is used.

3.3.2. Disease control rate.

A total of 991 patients were included in the analysis of DCR. The TKIs treatment group was associated with better DCR (OR: 2.54, 95% CI: 1.27–5.08, P = .009), but significant heterogeneity was found in the DCR analysis among the studies (Chi2 = 31.18, df = 8 [P = .0001]; I2 = 74%, Figure 2).

Figure 2.

Figure 2.

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Assessment of Disease Control Rate (DCR). The diamond indicates best estimate of the true (pooled) outcome (with width indicating 95% CI); experimental stands for tyrosine kinase inhibitors (TKIs); control stands for placebo. Since there is a high heterogeneity, a random-effects model is used.

3.3.3. Progression-free survival (PFS).

The PFS analysis included 1033 patients from 6 clinical studies. Overall, the HR was 0.46 (95% CI: 0.34–0.62; P < .00001), indicating that TKIs have therapeutic effects in treating patients with advanced or metastatic sarcoma who have failed chemotherapy. However, the analysis showed significant heterogeneity (Chi2 = 24.81, df = 9 [P = .003]; I2 = 64%, Figure 3).

Figure 3.

Figure 3.

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Assessment of Progression-Free Survival (PFS). The diamond indicates best estimate of the true (pooled) outcome (with width indicating 95% CI); experimental stands for tyrosine kinase inhibitors (TKIs); control stands for placebo. Since there is a high heterogeneity, a random-effects model is used.

Furthermore, in subgroup analysis, a significant advantage of TKIs in prolonging PFS was observed in the cohorts of leiomyosarcoma (HR: 0.35, 95% CI: 0.23–0.53, P < 0. 0001), SS (HR: 0.22, 95% CI: 0.11–0.45, P < .0001), osteosarcoma (HR: 0.35, 95% CI: 0.20–0.64, P = .0006), and non-adipocytic sarcoma (HR: 0.76, 95% CI: 0.62–0.94, P = .001). However, the result was not statistically significant in the cohorts of liposarcoma (HR: 0.87, 95% CI: 0.56–1.34, P = .53), ASPS (HR: 0.36, 95% CI: 0.06–2.02, P = .24), and chondrosarcoma (HR: 0.55, 95% CI: 0.22–1.38, P = .20, Figure 4).

Figure 4.

Figure 4.

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Assessment of Progression-Free Survival (PFS) of subgroups. The diamond indicates best estimate of the true (pooled) outcome (with width indicating 95% CI); experimental stands for tyrosine kinase inhibitors (TKIs); control stands for placebo. Since there is a high heterogeneity, a random-effects model is used.

3.3.4. Overall survival.

ALTER0203 was excluded from the analysis as it did not provide OS values or survival curves. A total of 800 patients were included in the analysis (in CASPS, the HR was extracted from the OS curve provided). The results showed that TKI treatment improved OS compared to placebo in patients with advanced or metastatic sarcoma who had already received standard chemotherapy but whose disease had progressed (HR: 0.80, 95% CI: 0.67–0.96, P = .02). No significant heterogeneity was identified in this analysis (Chi2 = 11.54, df = 8 [P = .17]; I2 = 31%, Figure 5).

Figure 5.

Figure 5.

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Assessment of Overall Survival (OS). The diamond indicates best estimate of the true (pooled) outcome (with width indicating 95% CI); experimental stands for tyrosine kinase inhibitors (TKIs); control stands for placebo. Since there is a low heterogeneity, a fixed-effects model is used.

In addition, the subgroup analysis showed that TKIs treatment led to a prolongation of OS in patients with ASPS (HR: 0.21, 95% CI: 0.07–0.63, P = .95) and in patients with non-liposarcoma (HR: 0.76, 95% CI: 0.62–0.94, P = .01). However, there was no significant difference in OS with the patients of liposarcoma (HR: 1.03, 95% CI: 0.44–2.40, P = .95), leiomyosarcoma (HR: 0.50, 95% CI: 0.24–1.04, P = .06), SS (HR: 0.87, 95% CI: 0.32–2.37, P = .78), osteosarcoma (HR: 0.74, 95% CI: 0.37–1.47, P = .39), and chondrosarcoma (HR: 1.06, 95% CI: 0.34–3.31, P = .92, Figure 6).

Figure 6.

Figure 6.

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Assessment of Overall Survival (OS) of subgroups. The diamond indicates best estimate of the true (pooled) outcome (with width indicating 95% CI); experimental stands for tyrosine kinase inhibitors (TKIs); control stands for placebo. Since there is a low heterogeneity, a fixed-effects model is used.

3.3.5. Sensitivity analysis and publication bias.

After conducting sensitivity analysis by removing one study at a time, it was found that the results of DCR and OS were unstable. To assess various indicators for each trial, qualitative assessment was performed using the Cochrane Bias Risk Tool and Sata software. Overall, these studies are considered to have a low risk of bias The outcome of the Egger test showed that the publication bias was low for all efficacy endpoints (efigure 4–7 in the Supplemental Content, http://links.lww.com/MD/L916; http://links.lww.com/MD/L917; http://links.lww.com/MD/L918; http://links.lww.com/MD/L919).

4. Discussion

Adriamycin is the first-line palliative chemotherapy for advanced STS. A retrospective analysis[35] concluded that chemotherapy may only benefit approximately 50% of patients with advanced STS. Notably, synovial sarcoma and liposarcoma subtypes have a better prognosis. Although conventional first-line chemotherapy may provide short-term survival benefits for patients with sarcoma, those with locally advanced and metastatic sarcoma still have poor long-term survival prospects. Several clinical trials[36,37] have shown that combination chemotherapy has not been shown to be superior to anthracycline monotherapy, and there is no evidence that combination chemotherapy is superior to anthracycline monotherapy. Therefore, the use of chemotherapy combinations as a first-line treatment for patients with advanced STS remains controversial. Multiple drug resistance and the side effects of chemotherapy remain a significant challenge. Resistance to conventional chemotherapy is the primary reason for treatment failure and tumor recurrence in sarcoma.[38,39] However, treating advanced or metastatic sarcomas after first-line treatment is not established and it is ineffective. An analysis[40] indicated that only 20% of patients with STS benefit from second-line chemotherapy, with a 23% PFS at 6 months and the median OS was 8 months (95% CI: 7–10 months). A Phase II trial (NCT01192633)[41] reported that the combination of gemcitabine, vincristine, and cisplatin (GVP) resulted in a median PFS of 4.8 months (95%CI: 0.1–9.5) and a median OS of 15.0 months (95%CI: 6.1–23.9) in locally advanced sarcoma patients treated with first-line chemotherapy. Another clinical trial[42] concluded that using high-dose ifosfamide (a total dose of 14 g/m2) as the second or third-line chemotherapy for patients with refractory bone and STS, the median OS was only 8.7 months and the overall DCR was 39%. The first-line treatment of locally advanced or metastatic sarcoma remains a complicated problem.

Fortunately, TKIs have made progress in the treatment of advanced or metastatic sarcoma, assisting patients in resolving their dilemma of medication. It is well known that TKIs have a broad range of pathways of action, and the majority of the drugs included in this meta-analysis are multi-target receptor TKIs. For instance, regorafenib involves targets such as RET, VEGFR1/2, KIT, FGFR1/2, RAF-1, BRAF (V600E), SAPK2, PTK5, BCR-ABL, CSFR1, and is sensitive to mCRC, GIST, and HCC.[43] Pazopanib has a wide range of targets, including VEGFR1/2/3, PDGFRα/β, FGFR1/3, KIT, Itk, Lck and c-Fma, and could be used to treat patients with STS.[44,45] However, due to the rarity and heterogeneity of sarcoma, TKIs remain a challenging treatment option.

For this purpose, we conducted a meta-analysis to evaluate the efficacy of TKIs therapy in patients with advanced or metastatic sarcoma who had received prior chemotherapy. After screening, we included a total of 6 randomized controlled clinical trials. In this analysis, the results showed that the use of TKIs as a second-line option for patients with advanced or metastatic sarcoma who have been treated with chemotherapy can improve ORR and DCR and extend PFS and OS.

It is important to point out that the results for DCR and OS in the sensitivity analysis showed instability, although our study showed a benefit for overall DCR and OS in sarcoma. A careful examination of these studies revealed that the primary source of instability in the analysis of DCR was the liposarcoma cohort. The poor efficacy of TKIs in liposarcoma resulted in a significant heterogeneity of the analysis of DCR. In addition, due to the heterogeneity of sarcomas, the efficacy of the same drug is not the same in different types of sarcomas, we performed subgroup analyses based on histological types of sarcomas for both PFS and OS. On the one hand, an increase in PFS was observed in the leiomyosarcoma, synovial sarcoma, osteosarcoma and non-adipocyte sarcoma subgroups with a very low level of heterogeneity. On the other hand, no PFS benefit was observed in the liposarcoma, ASPS and chondrosarcoma cohorts. Heterogeneity was mainly due to different targets and mechanisms of TKIs, and the sample size of included studies was insufficient, resulting in bias. In particular, we found that anlotinib had a significant effect on liposarcoma and ASPS. The use of anlotinib can be considered for the treatment of liposarcoma and ASPS because there are limited medicines for the treatment of liposarcoma and ASPS and their effectiveness is not satisfactory, but regorafenib is not recommended.

The instability of the sensitivity analysis for OS may be due to the fact that all trials except PALETTE allowed patients to cross over after disease progression, which affects the assessment of OS. In addition, after performing a subgroup analysis on OS, we discovered noteworthy improvements in OS for patients with ASPS and non-liposarcoma who received treatment with TKIs. However, we observed no significant differences in OS for patients with liposarcoma, leiomyosarcoma, synovial sarcoma, osteosarcoma, and chondrosarcoma. The results of the OS subgroup analysis should be taken with caution due to crossover. Adequate studies will be needed to confirm the benefit of TKI in OS.

There are some limitations that must be taken into account. First, because of the rarity of sarcomas, some clinical trials have included small numbers of patients. Furthermore, subtypes of sarcoma, especially rare histologic subtypes, were not included enough. Therefore, it is of vital importance to include more sarcomas with rare histological subtypes in further clinical trials. Secondly, the conclusions drawn from the subgroup analysis should be interpreted with caution because of the cross over effect. Finally, some discrepancies may occur due to the calculation of data from some of the included studies.

Nevertheless, for patients with advanced or metastatic sarcoma who have received prior chemotherapy, our study continues to support the use of TKIs as a second-line treatment option. The results of this study confirm the achievements of TKIs in the improvement of ORR and prolongation of PFS, highlighting the potential of TKIs in the treatment of sarcoma. It also complements the second-line regimen for patients with advanced or metastatic sarcoma who have previously received chemotherapy.

Based on the fact that some sarcomas are driven by characteristic cytogenetic or molecular alterations,[46] using cytogenetic, molecular, and immunohistochemical testing in diagnosis improves the diagnostic efficiency of sarcomas and helps to select therapeutic regimens. The most common mutations found in sarcoma genomics are cell cycle control genes, TP53, receptor TKs, PI3K, RAS, and epigenetic regulators; subtype-specific associations include TERT amplification in endosarcoma and SWI/SNF alterations in uterine adenosarcoma.[47,48] Genomic testing has subdivided the histologic subtypes of sarcomas into various genetic subtypes to facilitate the development of new drugs and new therapeutic options. Several case reports of the use of ALK-TKIs for the treatment of PRRC2B-ALK rearranged epithelioid inflammatory myofibroblastic sarcoma provide successful examples of the durable efficacy of targeted therapy.[49,50] In the follow-up analysis of the REGOSARC study,[51] which was included in our meta-analysis, no meaningful prognostic and predictive biomarkers for response to regorafenib treatment were found. But mutations in genes associated with angiogenesis were found in this study, suggesting the feasibility of an anti-angiogenic targeted therapy. It is expected that future improvements in cytogenetic and molecular diagnostic methods will support the continued development of targeted drug therapy for sarcoma.

Based on existing research, second-line chemotherapy has poor efficacy while second-line treatment with TKIs shows more promise, our systematic evaluation and analysis suggests that TKIs may be a promising choice for second-line treatment after chemotherapy. Regorafenib and pazopanib are recommended for use in patients with non-liposarcoma subgroups, such as leiomyosarcoma, synovial sarcoma, and osteosarcoma, but are not recommended for liposarcoma and ASPS. On the contrary, we found that anlotinib was more effective in liposarcoma and ASPS, and recommend it as a second-line treatment option for liposarcoma and ASPS.

In addition, we have discovered the prospect of treating sarcoma in some combination therapies. The phase II trial PAPAGEMO[52] showed that the combination of pazopanib with gemcitabine significantly prolonged median PFS in STS patients who had previously failed chemotherapy, but did not significantly increase median OS compared to pazopanib monotherapy. Results from other cohorts in ALTER 0203[53] also showed that compared to anlotinib monotherapy, the combination of anlotinib with other therapies not only improves ORR and median PFS but also prolongs median OS. Based on these studies, combination therapy appears to be a promising treatment strategy. Another clinical trial[54] compared the safety and effectiveness of gemcitabine plus pazopanib (G + P) and gemcitabine plus docetaxel (G + T). The results suggest that G + P can replace G + T for patients with non-adipocytic STS. Moreover, previous studies have demonstrated the potential benefits of combining TKIs and immune checkpoint inhibitors in treating advanced or metastatic sarcoma.[20,55] Several clinical trials (NCT05679921, NCT04172805) are underway to evaluate the combination of TKIs and immunotherapy, and these results are expected to provide more reliable evidence for combination therapy. We believe that the combination of TKIs with other conventional therapies is a promising novel therapy. Implications of combination therapy with TKIs can be further investigated in the clinical management of sarcomas. We look forward to further updates on the results of clinical trials and the refinement of the mechanism of action of TKIs in sarcoma to provide a deeper understanding of the efficacy of TKIs in the treatment of advanced STS. Meanwhile, with the elucidation of the cytogenetic and molecular pathogenic basis of various histological subtypes of sarcoma, targeted therapy of sarcomas will be individualized and precise, and treatment of sarcomas will move into a promising new era.

5. Conclusions

In patients with advanced or metastatic sarcoma, TKIs have advantages in increasing ORR, DCR, PFS, and OS. It is possible to consider using multi-target TKIs as a second-line treatment after chemotherapy has already been attempted. To ensure effective treatment, it is important to select specific TKIs based on the histological subtypes of the sarcoma.

Author contributions

Conceptualization: Zhanpeng Liang.

Data curation: Wenxia Li.

Methodology: Liwen Liu, Huatang Zhang.

Project administration: Liwen Liu, Huatang Zhang, Cantu Fang.

Software: Jiaming Wu.

Supervision: Jiaming Wu.

Validation: Huiqin Lai.

Writing – original draft: Wenxia Li.

Writing – review & editing: Zhanpeng Liang.

Supplementary Material

medi-103-e37423-s003.docx (43.5KB, docx)

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Abbreviations:

ASPS
alveolar soft part sarcoma
CI
confidence interval
DCR
disease control rate
GIST
gastrointestinal stromal tumors
HR
hazard ratio
OR
odds ratio
ORR
objective response rate
OS
overall survival
PFS
progression-free survival
RFS
recurrence-free survival
SS
synovial sarcoma
STS
soft tissue sarcoma
TKIs
tyrosine kinase inhibitors
TKs
tyrosine kinases.

Supplemental Digital Content is available for this article.

The authors have no funding and conflicts of interest to disclose.

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

How to cite this article: Li W, Liu L, Liang Z, Lai H, Wu J, Zhang H, Fang C. Efficacy of tyrosine kinase inhibitors in patients with advanced or metastatic sarcomas after prior chemotherapy: A meta-analysis. Medicine 2024;103:11(e37423).

Contributor Information

Wenxia Li, Email: 1271173928@qq.com.

Liwen Liu, Email: llwllwllw8015@163.com.

Zhanpeng Liang, Email: 945722672@qq.com.

Huiqin Lai, Email: lhq2646592073@163.com.

Jiaming Wu, Email: 454247314@qq.com.

Huatang Zhang, Email: 2567406154@qq.com.

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