First-Line Anlotinib Treatment for Soft-Tissue Sarcoma in Chemotherapy-Ineligible Patients: An Open-Label, Single-Arm, Phase 2 Clinical Trial

Soft-tissue sarcoma (STS) is a mesenchymal malignancy with approximately 70 histopathological subgroups (1), with liposarcoma being the most common subtype accounting, for about 15% of all STS cases (2). Most patients with STS undergo surgery as the primarily treatment. However, for locally advanced or metastatic STS (LA/M STS), systemic treatment is considered to be the only therapeutic approach, with chemotherapy based on anthracyclines and ifosphamide the usual first-line treatment regimen (3, 4). However, patients with LA/M STS have poor prognosis, with a reported 5-year survival rate of only 27.2% for advanced STS in a large Korean cohort, though it should be noted that 65.6% of these patients received chemotherapy (5). The median progression-free survival (PFS) of first-line chemotherapy was limited to 5 to 7 months and the median overall survival (OS) was around 20 months (6, 7). In addition to unsatisfactory first-line treatments, there have always been cases of patients refusing chemotherapy on first diagnosis or of doctors judging that they would not be able to tolerate chemotherapy. New drugs with a better efficacy and safety profile are urgently needed to treat these patients. In recent years, treatment options for advanced STS have focused on anti-angiogenic therapy, with multikinase inhibitors becoming the major drug class, based on the results of preliminary studies (8–11).

Anlotinib inhibits tumor cell proliferation and angiogenesis as well as inducing apoptosis by simultaneously targeting VEGFR, FGFR, PDGFR, and c-Kit (12–15). Previous studies reported median PFS times of 6.27 and 5.6 months for patients with advanced STS who received anlotinib after failure of standard therapy (16, 17). In a trial of second-line treatment, a retrospective analysis encompassing approximately 30 pathological subtypes revealed that the median PFS, OS, and objective response rate (ORR) of patients who received anlotinib monotherapy were 6.1, 16.4, and 13.4%, respectively (18). On the basis of the ALTER0203 trial (17), a phase 2b clinical trial of anlotinib for the treatment of advanced STS, the National Medical Products Administration in June 2019 gave approval for the use of anlotinib, an innovative drug independently developed in China, for second-line treatment of STS. In 2021, the sarcoma expert group of the Chinese Society of Clinical Oncology raised the recommendation and evidence levels of anlotinib to a grade I recommendation and Class 1A evidence, respectively.

On the basis of reliable clinical data on the use of anlotinib for second-line therapy of STS, a phase 2 clinical trial was designed with the aim of using anlotinib to treat different subtypes of LA/M STS but without chemotherapy. The aims were to establish prospectively the efficacy and safety of first-line treatment of LA/M STS subtypes with anlotinib, thereby providing a more precise and optimized treatment regimen for prolonging the survival of these very ill patients.

This was a single-arm, multicenter, prospective trial conducted between April 2019 and June 2022. A total of patients with 40 LA/M STS who were chemotherapy-naive or likely to be intolerant to chemotherapy as judged by the investigators, were selected from the Departments of Bone and Soft Tissue Oncology in 7 hospitals across China.

The major criteria for inclusion in the trial were: (i) Patients of age 18 to 70 years regardless of gender; (ii) LA/M STS diagnosed by pathology according to the 2016 WHO classification of STS. Pathological types included: hemangiosarcoma (HSA), liposarcoma, leiomyosarcoma (LMS), synovial sarcoma (SS), undifferentiated pleomorphic sarcoma (UPS), and other sarcomas [specifically, malignant peripheral nerve sheath tumor (MPNST), fibrosarcoma (FS), clear cell sarcoma (CCS) and others], except for the following: Alveolar soft part sarcoma, rhabdomyosarcoma, chondrosarcoma, osteosarcoma, gastrointestinal stromal tumor, dermatofibrosarcoma protuberans, Ewing sarcoma/primary neuroectodermal tumor, inflammatory myofibroblastoma and malignant mesothelioma; (iii) had not received antitumor drug therapy or patients were >6 months after previous neoadjuvant or adjuvant chemotherapy ceased; (iv) patients who refused chemotherapy or were unlikely to tolerate chemotherapy as judged by the investigators based upon age or co-morbidities; (v) measurable lesions according to RECIST ver. 1.1 criteria (19); and (vi) an Eastern Cooperative Oncology Group performance status (ECOG PS) score between 0 and 2, and expected time of survival >3 months. Physical examinations included vital signs, routine blood chemistries and hematological tests, 12-lead ECG, and echocardiography.

The major exclusion criteria were: (i) qualified for cytotoxic chemotherapy and willing to accept chemotherapy; (ii) a previous history of STS chemotherapy before enrollment (patients could be enrolled if the adjuvant or neoadjuvant chemotherapy had been completed >6 months before enrollment); (iii) had previously received anlotinib or other small-molecule anti-angiogenic tyrosine kinase inhibitor drugs, or various anti-angiogenic mAb drugs; (iv) had antitumor treatment within the first 4 weeks of enrollment; (v) had other malignancies within the previous 5 years; and (vi) known central nervous system metastasis. Supplementary File S1 lists all of the inclusion and exclusion criteria in detail.

Anlotinib was given orally at a dose of 12 mg once daily from days 1 to 14 every 3 weeks. Medication continued until disease progression (PD) that was evaluated on the basis of efficacy assessment criteria, poor compliance with medication use outside the range 80% to 120% of the prescribed dose, patient withdrawal of informed consent, treatment with other antitumor drugs that may have affected the efficacy assessment (e.g., chemotherapy, targeted therapy or biotherapy), unexpected pregnancy, intolerable adverse events (AE) or serious AEs confirmed by the investigator or termination of treatment as deemed appropriate by the treating physician in the best interest of the patient. Protocol-recommended dose modifications were made in response to AEs.

Before treatment, all patients underwent tumor baseline and safety indicator examinations. Efficacy evaluation (CT/MRI) was performed initially 3 weeks after treatment and efficacy was confirmed at 6 weeks. CT/MRI was performed every 2 cycles after medication. The time of determination of the ECOG PS and quality of life scores were consistent with imaging examinations. AEs were documented for ≥30 days after the last medication and follow-up was conducted until AEs were relieved or stabilized. Follow-up of any subsequent treatment and the survival status of patients were conducted every 8 weeks through outpatient visits or telephone calls after the last drug administration.

The primary endpoint was PFS evaluated by investigators, with PFS being the time from patient enrollment to PD or death.

Secondary endpoints were OS (time from the initiation of anlotinib treatment to death), ORR defined as the sum of the complete response (CR) and partial response (PR) proportions, disease control rate (DCR) [sum of CR, PR, and stable disease (SD) proportions]. Treatment efficacy was assessed once every 2 treatment cycles according to RECIST ver. 1.1 criteria (19).

AEs were rated according to NCICTCC ver. 4.0 guidelines during the trial, and ultimately the investigators decided whether they were treatment-related.

This phase 2 trial was performed in accordance with the provisions of the Declaration of Helsinki and the International Conference on Harmonization guidelines for Good Clinical Practice, and was approved by the institutional review boards of the participating hospitals. All patients provided signed written informed consent before enrollment. The trial was registered at clinicatrials. gov (NCT03792542).

According to an analysis of the published literature, the reference value for PFS for first-line doxorubicin treatment of STS is 4.60 months (6, 20). Assuming that anlotinib was superior to doxorubicin treatment, PFS was extended by 40% and the PFS in the anlotinib group was 6.44 months, α = 0.15, β = 0.8, analyzed using PASS15 software, with the sample size being 39 cases enrolled in the anlotinib group. This trial aimed to enroll 44 patients considering a 10% drop-out rate, and a required endpoint event of 33. The data were statistically analyzed using SPSS ver. 19.0 (IBM, RRID:SCR_002865) at a 95% confidence interval (CI), with a P value of <0.05 being regarded as statistically significant. Categorical data are expressed as percentages, and normally distributed variables as the mean ± standard deviation. Kruskal–Wallis H and χ² tests were used to compare continuous variables and categorical data across the two groups, respectively. The log-rank test was used to compare the survival occurrences among the various groups. An evaluation of the AEs detected during the trial was performed using a descriptive statistical technique. On the basis of the full analysis set (FAS), an efficacy analysis was conducted. The median PFS and OS were estimated using the Kaplan–Meier method, yielding bilateral 95% CIs. Percentages are given for DCR and ORR, together with 95% CIs.

The safety analysis was based on the safety analysis set. Treatment-related AEs (TRAE) are described in frequency tables and as percentages.

The data generated in this trial are not publicly available due to restrictions of information that could compromise patient privacy and/or consent but are available upon reasonable request from the corresponding author. Please contact the corresponding authors for requests of deidentified raw data.

Between April 2019 and June 2022, of 43 patients assessed a total of 40 were enrolled in the trial. The median age of patients was 57.5 years with 60.0% (n = 24) being male. The subtypes included liposarcoma (n = 10), UPS (n = 8), FS (n = 8), SS (n = 4), MPNST (n = 3), LMS (n = 3), CCS (n = 1), HSA (n = 1), and others (n = 2). Most patients were in stage IV (85.0%) and had a surgical history (95.0%) as well as 85.0% patients who had ≤ 2 metastatic organs. In this trial, a total of 10 patients with liposarcoma were included, comprised of 5 high-grade myxoid liposarcoma (MLPS) and 4 dedifferentiated liposarcoma (DDLPS) cases and 1 well-differentiated liposarcoma (WDLPS) case. Among them, the WDLPS individual dropped out before completing one cycle of treatment (Table 1 ).

The representativeness of the patients is shown in Supplementary Table S1.

Forty patients were subsumed in the FAS and safety analysis sets. Median follow-up of PFS was 12.81 months (95% CI, 4.11–37.22) and 36.04 months (95% CI, 27.53–38.31) for OS. From the data cutoff date of August 2023, 9 patients withdrew their informed consent, 3 withdrew due to AEs, 23 were discontinued due to PD, 1 visit exceeded the scheduled window due to COVID-19, 2 died for reasons unrelated to PD, and 2 withdrew based on the investigator’s assessment. In addition, there were 18 patient deaths and 4 patients who were lost to contact, whereas 18 patients were under survival follow-up (Fig. 1). Finally, according to the inclusion and exclusion criteria, a total of 32 patients declined chemotherapy and 8 were deemed not suitable for chemotherapy. The Multidisciplinary Team assessed and concluded that these 8 individuals were unable to tolerate first-line chemotherapy.

The median PFS was 6.83 months (95% CI, 4.17–8.71; Fig. 2A ). For subgroups, the median PFS was 8.71 months (95% CI, 1.48–8.71) and 6.83 months (95% CI, 4.17–9.69), respectively, for liposarcoma and other subtypes (Table 2 , Fig. 2B ). In terms of secondary endpoints, the median OS was 27.40 months [95% CI, 16.43–not evaluable (NE); Fig. 2C ]. For subgroups, the median OS was 16.23 months (95% CI, 1.54–NE) for patients with liposarcoma and not reached (NR) for other subgroups (95% CI, 16.89–NE; Table 2 , Fig. 2D ).

The time to response and the duration of treatments are shown in Fig. 3A. Among the 40 patients in the FAS, PR occurred in 1 patient (2.5%) and 26 (65.0%) attained SD. Confirmed ORR was 2.5% (95% CI, 0.1%–13.2%) and DCR 67.5% (95% CI, 50.9%–81.4%; Table 3 ). The greatest changes in lesion sizes among the 37 patients are shown in Fig. 3B , whereas 13 patients exhibited a tumor shrinkage range from 0% to 50%. Figure 3C  displays the percentage changes over time, with 1 patient showing a range between 0% and 10% for up to 37 months. For liposarcoma and the other subgroups, ORRs were 0.0% and 3.3%, and DCRs 50.0% and 73.3%, respectively (see Table 2 ).

Thirty-seven (92.5%) patients experienced at least one TRAE, the most common being hyperthyroidism (47.5%), hypertension (45.0%), proteinuria (37.5%), hypertriglyceridemia (25.0%), hand-foot skin reaction (22.5%), and fatigue (20.0%; Supplementary Table S2). Ten (25.0%) patients had ≥ grade 3 or 4 TRAEs, with 6 (15.0%) cases of hypertension, 3 (7.5%) of proteinuria and others that only occurred once (2.5%). No deaths occurred due to the treatment regimen. Six (15.0%) patients had to stop treatment due to AEs and the incidence of AEs led to dose reductions in 3 (7.5%) patients.

Anthracycline chemotherapy is the gold standard first-line treatment for LA/M STS (21). The median PFS time for patients receiving first-line chemotherapy was 5 to 7 months and the median OS circa 20 months (22, 23). In the present trial, anlotinib monotherapy was chosen as the alternative first-line treatment for anthracycline-naive adults with LA/M STS, which led to a median PFS of 6.83 months and OS of 27.40 months, whereas ORR and DCR were 2.5% and 67.5%, with no new TEAEs identified. When compared with doxorubicin alone as first-line treatment in patients with advanced STS, a median PFS of 5.5 months has been reported (24).

In another study about first-line treatments for metastatic STS, pazopanib and doxorubicin were administered to 81 and 39 patients, respectively, and the PFS was non-inferior (HR, 1.00; 95% CI, 0.65–1.53) in the pazopanib group. The ORR for pazopanib and doxorubicin were 12.3% and 15.4%, with PFS under doxorubicin treatment 5.3 month (95% CI, 1.7–8.2), and PFS under pazopanib treatment 4.4 month (95% CI, 2.7–6.0; ref. 25). In a study of pazopanib as monotherapy for first-line treatment of LA/M STS the median PFS reached 3.67 months, with a median OS of 14.16 months (26). The phase 3 PALETTE trial evaluated pazopanib in the second-line setting and found a median PFS of 4.6 months and an OS of 12.5 months (27).

Assessing the results together, anlotinib monotherapy as first-line STS treatment, with a PFS time of 6.83 months was shown to be noninferior to the historical use of first-line agents, including doxorubicin with a 5 to 7 months PFS (22, 23) and ifosfamide with a 2.52 month PFS, as well as pazopanib with a 3.67 month PFS. In a previous trial, the median PFS was 3.7 months for dedifferentiated advanced liposarcoma after first-line combination therapy with anlotinib and epirubicin (28). In the present phase 2 trial, the median PFS and OS of patients with liposarcoma (n =10) reached 8.71 and 16.23 months under first-line monotherapy treatment, respectively, that implied the promising efficacy of anlotinib for the treatment of liposarcoma. The findings were superior to that of the liposarcoma subgroup (n = 13) in a phase 2 trial of second-line treatment with anlotinib for LA/M STS (median PFS and OS were 5.6 and 13.0 months, respectively; ref. 16), which was similar to the 4.5 months PFS of patients with WDLPS or DDLPS treated with the CDK4 inhibitor palbociclib as first and second-line therapies. It should be noted that all patients in that trial were CDK4 amplification positive (29). In addition, STS that are rare malignancies of mesenchymal origin, in the present trial revealed 15% of patients having ≥2 metastatic organs, but it is not clear whether the number of metastatic organs of STS was related to the survival outcomes with anlotinib; but patients with three or more sites of metastases exhibited shorter median PFS (3.1 vs. 3.6 months) and OS (5.7 vs. 23.8 months) compared with only one metastatic site when patients with STS treated with trabectedin (30).

Most of the common TRAEs were consistent with the phase 1 trial results of anlotinib therapy against advanced refractory solid tumors (31). They included hypertension, triglyceride, and cholesterol elevation, hand and foot skin reactions, and fatigue. Grade 3–4 TRAEs, including hypertension, proteinuria, hand and foot skin reactions and fatigue were also in line with the common specific AEs elicited by anlotinib monotherapy in patients with advanced STS (32). In the presence of close monitoring of lipid level and blood pressure, these TRAEs were considered to be manageable and alleviated with appropriate clinical interventions. In contrast, the commonly used doxorubicin combined with ifosfamide treatments of STS led to essential myelosuppression, with high incidences of grade 4 leukopenia in addition to anemia and thrombocytopenia. There was a discontinuation rate of 27.1% and also cases of toxic death (33).

There were some limitations to the present trial. First, selection bias cannot be ruled out in single arm, non-randomized trials, and considering that patients were from a Chinese population, the results might not be generalizable to other ethnic populations. Second, due to the small cohort of patients enrolled, the power of the statistical tests may have been limited. Nevertheless, the results of this trial provide preliminary promising evidence for the use of first-line therapy with anlotinib for patients with LA/M STS. Third, the preliminary results of anlotinib as first-line treatment for selective STS were intriguing, but a randomized trial, including an SS cohort, may be needed in the near future to validate our tentative conclusions. Of note, the results of this trial also found significant tumor shrinkage for this histological subtype. The fourth limitation lies in our use of 4.6 months as a baseline reference point for efficacy, which was derived from Dr. Judson’s study (EORTC 62012; ref. 20). Despite several later-phase 3 studies [ANNOUNCE (7), PICASSO (34), and SARC021 (35)] that demonstrated prolonged PFS with doxorubicin alone, due to the consideration of a potentially small sample size in our trial, we still opted to use the PFS 4.6 months value as a reference for efficacy. Although the PFS of our trial results is longer than that reported in the current literature, we recognize this limitation and intend to address it in further research by conducting a more comprehensive randomized clinical trial. Our particular focus will be on comparing the efficacy of anlotinib as first-line treatment for highgrade liposarcoma, LMS, and SS.

After a median 29.1 month follow-up time, the median OS was found to be 27.4 months. More data will be reported after obtaining long-term survival information in the near future. Taken together, despite the limited number of patients with liposarcoma participating in the trial, the results still provides some promising preliminary data.

First-line anlotinib monotherapy demonstrated favorable efficacy in the treatment of LA/M STS, comparing with conventional chemotherapies, whereas particularly for patients with liposarcoma who are generally difficult to treat, the prolongation of median PFS was encouraging. Toxicity was also manageable and acceptable.

No disclosures were reported.

The funders had no role in the trial design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication.

T. Li: Conceptualization, data curation, writing–original draft, writing–review and editing, design of the work. Y. Dong: Data curation, writing–review and editing. Y. Wei: Data curation, writing–review and editing. S. Wang: Data curation, writing– review and editing. Y. Liu: Data curation, writing–review and editing. J. Chen: Data curation, writing–review and editing. W. Xiong: Data curation, writing–review and editing. N. Lin: Data curation, writing–review and editing. X. Huang: Data curation, writing–review and editing. M. Liu: Data curation, writing–review and editing. X. Yan: Data curation, writing–review and editing. Z. Ye: Conceptualization, data curation, funding acquisition, writing–original draft, writing–review and editing, design of the work. B. Li: Conceptualization, data curation, funding acquisition, writing–original draft, writing–review and editing, design of the work.

This trial was supported by Chia Tai Tianqing Pharmaceutical Group Co., Ltd., Physician Elite in Training Scholarship of Zhejiang University (grant number 171132002), National Natural Science Foundation of China (grant number 81802684 and 82172688, to B. Li), and Key Project of Zhejiang Provincial Medical Science Program (grant number WKJ-ZJ-2308, to Z. Ye).