Advancing treatment efficacy: combined therapy of eribulin,anlotinib,and camrelizumab in advanced or metastatic retroperitoneal liposarcoma

Abstract

Background:

Retroperitoneal liposarcoma (RLPS) typically shows limited response to standard chemotherapy, presenting a challenge in treating advanced or metastatic RLPS.

Objective:

This study aimed to evaluate the potential advantages of a combined therapeutic strategy utilizing eribulin, anlotinib, and camrelizumab.

Design:

Between December 2020 and March 2023, this retrospective study enrolled patients with advanced or metastatic RLPS who received treatment at Peking University Cancer Hospital Sarcoma Center. The treatment regimen involved eribulin plus anlotinib and camrelizumab administered every 3 weeks (Q3W).

Methods:

Efficacy was assessed following the Response Evaluation Criteria in Solid Tumors version 1.1, while safety was evaluated using the Common Terminology Criteria for Adverse Events version 5.0.

Results:

The study included 47 patients with RLPS with a median age of 55.5 years. Patients received a median of 4.5 (range, 2–21) cycles of treatment. Notably, partial response was observed in 8 patients (18.2%), while 25 (56.8%) exhibited stable disease. The objective response rate (ORR) and disease control rate were 18.2% and 75%, respectively. Significant differences in ORR were observed among histological subtypes (well-differentiated vs de-differentiated vs myxoid: 0 vs 17.9% vs 50%; p = 0.039). Six patients underwent surgery before disease progression, and one patient with myxoid liposarcoma (MLPS) had a pathological complete response. With a median follow-up of 21.8 (range, 2.7–30.7) months, the median progression-free survival (mPFS) was 6.9 (95% confidence interval (CI), 4.7–9.1) months, and the 6-month PFS rate was 60.5%. Based on various histological subtypes, the mPFS was 8.4 (95% CI, 4.1–12.7) months with well-differentiated liposarcoma, 5.8 (95% CI, 3.3–8.3) months with de-differentiated liposarcoma and not reached with MLPS, respectively. Treatment-related adverse events (TRAEs) of any grade occurred in 36 (76.6%) patients, with grade 3 or higher TRAEs in 21 (44.7%) patients. The most common TRAEs were neutropenia (53.2%), proteinuria (21.3%), and anorexia (21.3%).

Conclusion:

The combined treatment strategy involving eribulin, anlotinib, and camrelizumab showed promising efficacy and manageable safety in patients with advanced or metastatic RLPS, particularly in those with MLPS.

Keywords

anlotinib camrelizumab combined therapy eribulin retroperitoneal liposarcoma

Introduction

Retroperitoneal soft tissue sarcomas (RSTs) encompass a rare and diverse array of tumors originating from mesenchymal cells, constituting approximately 10% of all soft tissue sarcomas (STSs).^1,2 Within the retroperitoneum, over 50 histologic subtypes have been identified. Among these, retroperitoneal liposarcomas (RLPSs) are the most prevalent, accounting for 45%–63% of cases.^2–6 Liposarcomas (LPSs) are classified into five histologic subtypes, each with distinct characteristics: well-differentiated liposarcoma (WDLPS) or atypical lipomatous tumor, de-differentiated liposarcoma (DDLPS), myxoid liposarcoma (MLPS), pleomorphic liposarcoma (PLPS), and myxoid pleomorphic liposarcoma (MPLPS).¹ Each subtype demonstrates distinct biological traits, recurrence patterns, metastatic risks, therapeutic effects, and prognoses.

WDLPS is a low-grade, locally aggressive neoplasm composed of proliferating mature adipocytes.⁷ It has a favorable outcome when complete resection is performed. Although WDLPS rarely metastasizes, there is a higher risk of local recurrence.⁸ DDLPS is a more aggressive, high-grade sarcoma with a higher risk of recurrence and metastasis. As a result, patients with DDLPS have a poor prognosis.^9,10 Primary retroperitoneal MLPS is rare, accounting for about 5% of all MLPS cases.¹¹ It is considerably more sensitive to chemotherapy and radiotherapy than WD/DDLPS.¹² PLPS is a high-grade sarcoma characterized by high invasion, metastasis, and recurrence. It is often insensitive to chemotherapy or radiotherapy.^1,12,13 MPLPS is an extremely rare adipocytic malignancy that preferentially involves the mediastinum of young patients.^1,14

Treatment options for LPS remain limited, with first-line therapies typically involving chemotherapy using doxorubicin, ifosfamide, or a combination of both. However, most LPS subtypes exhibit resistance to conventional treatment. As a result, more new effective treatment options are urgently needed for LPS patients.

Recent clinical trials have explored novel treatments for LPS, including innovative chemotherapies, targeted therapies, and immunotherapies. Eribulin (eribulin mesylate), derived from the marine natural product halichondrin B, is a microtubule-targeting agent. It exerts its action by binding strongly to microtubule plus ends, thereby suppressing dynamic instability. Currently, eribulin has gained approval for managing unresectable or metastatic LPS in patients who have previously received anthracycline-containing chemotherapy.

In a randomized phase III trial comparing eribulin to dacarbazine in patients with advanced LPS and leiomyosarcoma, eribulin notably improved overall survival (OS) among LPS patients. Despite a low objective response rate (ORR) of 4%,¹⁵ subgroup analyses of eribulin’s activity in advanced LPS indicated significant improvements in both OS and progression-free survival (PFS) compared to dacarbazine.¹⁶ The LEADER study demonstrated promising results for the combination of lenvatinib and eribulin in a limited patient cohort.¹⁷ Nevertheless, further research is essential to comprehensively evaluate the efficacy and safety of this treatment in a larger patient population.

Anlotinib, an orally administered tyrosine kinase inhibitor (TKI), targets vascular endothelial growth factor receptor, fibroblast growth factor receptor, platelet-derived growth factor receptor, and c-kit, thereby inhibiting both tumor angiogenesis and tumor cell proliferation.^18,19 Clinical trials have shown its efficacy in improving PFS and OS among patients with refractory metastatic STSs. Within the spectrum of STSs, anlotinib achieved an ORR of 13%, with a specific ORR of 7.7% in LPS subtypes.²⁰ In addition, in a phase II trial, anlotinib displayed promising efficacy as a maintenance treatment post-initial anthracycline-based chemotherapy, showing an ORR of 12% in LPS patients.²¹

Despite the revolutionary impact of immune checkpoint inhibitors (ICIs) in cancer treatment, their application in advanced STSs has been limited due to poor immune cell infiltrates.^22–24 Pembrolizumab had an ORR of 18% in advanced STSs in the SARC028 trial.²⁵ Combining ICIs with TKIs has shown the potential to improve the effectiveness of immunotherapy while reducing the risk of immune-related adverse events (irAEs).^26,27 A single-center retrospective analysis combining ICIs with TKIs in advanced STSs revealed an ORR of 36.3% in patients with DDLPS, with one patient achieving a pathological complete response (pCR).²⁸ Similarly, a study from our department investigating anlotinib and camrelizumab in treating RSTs showed an ORR of 13.3% among LPS patients.²⁹

Building upon these findings, this study was initiated at our center to assess the efficacy and safety of eribulin in combination with anlotinib and camrelizumab for treating patients with advanced or metastatic RLPS.³⁰ The study sought to evaluate the potential benefits of this combination therapy.

Methods

Study design and patients

Between December 2020 and March 2023, this single-center retrospective study reviewed patients with advanced or metastatic RLPS who received treatment with eribulin, anlotinib, and camrelizumab at the Sarcoma Center of Peking University Cancer Hospital. We included patients 18 years of age and older with histologically confirmed locally advanced, locally recurrent, or metastatic RLPS; with adequate bone marrow, renal, and hepatic function; regardless of prior treatment history. Patients with histologically proven subtypes of retroperitoneal sarcoma other than RLPS were excluded.

All patients provided written informed consent, and the study followed the Declaration of Helsinki, guidelines for Good Clinical Practice, and local regulations on clinical trials. The study was approved by the Institutional Review Board of Peking University Cancer Hospital medical ethics committee (2022KT84).

Treatments

Before treatment initiation, all patients underwent baseline assessments including chest imaging evaluated by chest computed tomography (CT) or positron emission tomography-CT, contrast-enhanced CT or magnetic resonance imaging (MRI) of the abdomen and pelvis within 30 days. In addition, a complete blood count (CBC), hepatic and renal function tests, as well as endocrine function assessments within 2 weeks, were required.

Eribulin was administered intravenously at a dose ranging from 0.7 to 1.4 mg/m² on both day 1 and day 8 of a 3-week cycle. In some cases, the dosage of eribulin was reduced by 25% for certain patients experiencing treatment-related adverse events (TRAEs) in the previous cycle, in accordance with the Common Terminology Criteria for Adverse Events (CTCAE v5.0). Anlotinib was orally administered at a daily dose of 12 mg with a schedule of 2 weeks on and 1 week off. Camrelizumab was administered intravenously at a dose of 200 mg on day 1 of each treatment cycle.

Outcomes and follow-up

Tumor response, according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), was assessed using contrast-enhanced CT or MRI every three cycles.³¹ Patients who underwent at least one response evaluation were included in the efficacy analysis.

The safety analysis set included these treated patients who had at least one post-baseline safety assessment. CBCs and biochemical tests were conducted before each treatment cycle. TRAEs were assessed and graded based on CTCAE v5.0.

Patients were recommended to undergo follow-up visits every three cycles (approximately 9 weeks) to assess clinical outcomes, including symptoms, physical examinations, and imaging assessments. Follow-up was maintained as long as the patient remained alive. PFS was defined as the duration from the baseline examination to the first documented disease progression, last follow-up, or death from any cause. OS was defined as the time from the baseline examination to the date of death, regardless of the cause.

Statistical analysis

The statistical cutoff date for all data analyses was October 13, 2023. Subtype differences were analyzed using Fisher’s exact or Pearson’s chi-squared test. Kaplan–Meier survival tests were used to assess OS and PFS, while the log-rank test assessed correlations between prognosis and tumor grade. The data processing and statistical analyses were conducted using SPSS version 26 (SPSS Inc., Chicago, IL, USA). Univariate and multivariate Cox proportional hazards models were utilized to analyze the relationship between clinicopathological parameters and PFS, using R Version 4.3.2. A two-sided p value <0.05 was considered significant, and a 95% confidence interval (CI) was calculated. The reporting of this study conforms to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement³² (Supplemental Material).

Results

Patient characteristics

The study collected data from a cohort of 47 RLPS patients who received combination therapy involving eribulin, anlotinib, and camrelizumab at our center. The study population included 24 (51.1%) males and 23 (48.9%) females, with a median age of 55.5 (range, 25–74) years. All participants had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0–2. The histologic subtypes consisted of WDLPS (n = 11), DDLPS (n = 30), and MLPS (n = 6). As per the Fédération Nationale des Centres de Lutte Contre Le Cancer (FNCLCC) grading system,³³ G1, G2, and G3 accounted for 19.1%, 34.0%, and 46.8% of RLPS cases, respectively. Among them, 40 (85.1%) patients presented with locally advanced disease, while 7 (14.9%) patients had distant metastases in the peritoneum (n = 2), liver (n = 1), lungs (n = 1), and bone (n = 3). Initially, unresectable RLPSs were observed in 2 (4.3%) patients, whereas the remaining 45 (95.7%) patients experienced recurrence or metastasis following prior surgery. Of these, 37 (78.7%) patients received the combination therapy as first-line treatment, while 10 (21.3%) patients received it as second-line treatment due to disease progression after doxorubicin-based chemotherapy. Detailed baseline characteristics are presented in Table 1.

Table 1.

Patient characteristics.

Variable	N = 47 (100%)
Median age (years), median(range)	55.5 (25–74)
Gender, n (%)
Male	24 (51.1)
Female	23 (48.9)
ECOG PS, n (%)
0	15 (31.9)
1	28 (59.6)
2	4 (8.5)
Histologic subtype, n (%)
Well-differentiated	11 (23.4)
De-differentiated	30 (63.8)
Myxoid	6 (12.8)
FNCLCC grade, n (%)
G1	9 (19.1)
G2	16 (34.0)
G3	22 (46.8)
Stage, n (%)
Locally advanced	40 (85.1)
Metastatic	7 (14.9)
Prior surgery, n (%)
Yes	45 (95.7)
No	2 (4.3)
Treatment, n (%)
First line	37 (78.7)
Second line	10 (21.3)

Data presented as n (%) unless otherwise noted; due to rounding, percentages might not total 100.

ECOG PS, Eastern Cooperative Oncology Group performance status; FNCLCC, Fédération Nationale des Centers de Lutte Contre le Cancer.

Treatment and safety

All patients received the combined treatment of anlotinib plus camrelizumab and eribulin. Eribulin was administered at different doses based on variations in the ECOG PS and drug tolerance, with 19 (40.4%) patients receiving a dose of 0.7–1.1 mg/m² and 28 (59.6%) patients receiving a dose of 1.1–1.4 mg/m². Nineteen (40.4%) patients discontinued treatment due to severe TRAEs. In addition, 8 (17.0%) patients had their eribulin dosage reduced, while 6 (12.8%) experienced dose interruptions. Among these, one patient required prednisone hormone therapy and discontinued camrelizumab due to grade 3 immune-related colitis. Another patient chose to discontinue treatment independently for over 3 months, leading to disease progression. The remaining four patients experienced dose interruptions with eribulin.

According to CTCAE v5.0, TRAEs of any grade occurred in 36 (76.6%) patients. The most common TRAEs included neutropenia (n = 25, 53.2%), proteinuria (n = 10, 21.3%), and anorexia (n = 10, 21.3%). Twenty-one (44.7%) patients experienced grade 3 or higher TRAEs, including 10 (21.3%) with neutropenia, 4 (8.5%) with fatigue, 2 (4.3%) with anorexia, 2 (4.3%) with oral mucositis, and 1 (2.1%) each with drug-induced liver injury, hypertension, palmar-plantar erythrodysesthesia syndrome, immune-related diarrhea/colitis, and thrombocytopenia. Neutropenia (n = 3, 6.4%) was the only grade 4 adverse event reported, and there were no TRAE-related fatalities. Table 2 provides a summary of the TRAEs.

Table 2.

Summary of treatment-related adverse events (N = 47).

TRAEs	Total, N (%)	Grade 1–2, N (%)	Grade 3–4, N (%)
Any adverse events	36 (76.6)	33 (70.2)	21 (44.7)
Neutropenia	25 (53.2)	15 (31.9)	10 (21.3)
Proteinuria	10 (21.3)	10 (21.3)	0
Anorexia	10 (21.3)	8 (17.0)	2 (4.3)
Fatigue	9 (19.1)	5 (10.6)	4 (8.5)
Drug-induced liver injury	6 (12.8)	5 (10.6)	1 (2.1)
Hypothyroidism	5 (10.6)	5 (10.6)	0
Telangiectasis	5 (10.6)	5 (10.6)	0
Vomiting	4 (8.5)	4 (8.5)	0
Palmar-plantar erythrodysesthesia syndrome	4 (8.5)	3 (6.4)	1 (2.1)
Thrombocytopenia	4 (8.5)	3 (6.4)	1 (2.1)
Hypertension	4 (8.5)	3 (6.4)	1 (2.1)
Immune-related diarrhea/colitis	3 (6.4)	2 (4.3)	1 (2.1)
Oral mucositis	3 (6.4)	1 (2.1)	2 (4.3)
Hyperthyroidism	1 (2.1)	1 (2.1)	0
Dysgeusia	1 (2.1)	1 (2.1)	0

Data presented as n (%) unless otherwise noted. Maximum grade per patient.

TRAEs, treatment-related adverse events.

Efficacy

Three patients with RLPS (one with WDLPS and two with DDLPS) out of the total 47 were excluded from the efficacy analysis as they only underwent one treatment cycle due to drug intolerance (n = 2) and the impact of the COVID-19 pandemic (n = 1). Among the 44 patients eligible for efficacy analysis, there were 10 (22.7%) with WDLPS, 28 (63.7%) with DDLPS, and 6 (13.6%) with MLPS. The median number of cycles per patient was 4.5 (range, 2–21), and none achieved complete response (CR). Outcomes were distributed as partial response (PR) in 8 (18.2%) patients, stable disease (SD) in 25 (56.8%), and progressive disease (PD) in 11 (25.0%) as per RECIST v1.1 criteria. The ORR and disease control rate (DCR) were 18.2% and 75.0%, respectively.

In the WDLPS subgroup, there were no PR cases, 8 (80.0%) SD cases, and 2 (20.0%) PD cases. Five (17.9%) patients with DDLPS and 3 (50.0%) with MLPS had PR. Meanwhile, 15 (53.6%) with DDLPS and 2 (33.3%) with MLPS showed SD, and 8 (28.6%) with DDLPS and 1 (16.7%) with MLPS had PD. The ORRs for patients with WDLPS, DDLPS, and MLPS were 0, 17.9%, and 50.0%, respectively, displaying a significant difference between the subgroups (p = 0.039). However, the DCRs among patients with WDLPS, DDLPS, and MLPS were 80.0%, 71.4%, and 83.3%, respectively, indicating no statistically significant difference (p = 0.889). Further detailed data are available in Table 3 and Figure 1.

Table 3.

Efficacy results of the histologic subtypes according to RECIST v1.1 (N = 44).

	Total	WDLPS	DDLPS	MLPS	p value
Best overall response, n (%)
PR	8 (18.2)	0	5 (17.9)	3 (50.0)
SD	25 (56.8)	8 (80.0)	15 (53.6)	2 (33.3)
PD	11 (25.0)	2 (20.0)	8 (28.6)	1 (16.7)
ORR, %	18.2	0	17.9	50.0	0.039
DCR, %	75.0	80	71.4	83.3	0.889

Data presented as n (%) unless otherwise noted; due to rounding, percentages might not total 100.

DCR, disease control rate; DDLPS, de-differentiated liposarcoma; MLPS, myxoid liposarcoma; ORR, objective response rate; PD, progressive disease; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease; WDLPS, well-differentiated liposarcoma.

Figure 1.

Waterfall plot for the response to eribulin plus anlotinib and camrelizumab in patients with retroperitoneal liposarcoma. The purple line represents the threshold for progressive disease. The green line represents the threshold for partial response. Red columns represent myxoid liposarcoma (MLPS), light blue columns represent de-differentiated liposarcoma (DDLPS), and dark blue columns represent well-differentiated liposarcoma (WDLPS).

In the subgroup analysis based on the FNCLCC grade system, the ORRs among patients with G1, G2, and G3 were 0, 20%, and 25%, respectively (p = 0.32). The DCRs among patients with G1, G2, and G3 were 77.8%, 60.0%, and 85.0%, respectively (p = 0.257). No significant difference was observed in ORR and DCR among these subgroups. Additional detailed data are presented in Table 4.

Table 4.

Efficacy results of the FNCLCC grade subgroups according to RECIST v1.1 (N = 44).

	Total	G1	G2	G3	p value
Best overall response, n (%)
PR	8 (18.2)	0	3 (20.0)	5 (25.0)
SD	25 (56.8)	7 (77.8)	6 (40.0)	12 (60.0)
PD	11 (25.0)	2 (22.2)	6 (40.0)	3 (15.0)
ORR, %	18.2	0	20.0	25.0	0.32
DCR, %	75.0	77.8	60.0	85.0	0.257

Data presented as n (%) unless otherwise noted; due to rounding, percentages might not total 100.

DCR, disease control rate; FNCLCC, Fédération Nationale des Centers de Lutte Contre le Cancer; ORR, objective response rate; PD, progressive disease; PR, partial response; RECIST, Response Evaluation Criteria in Solid Tumors; SD, stable disease.

Follow-up and survival

Six out of the 44 cases included in the efficacy analysis underwent surgery before experiencing disease progression. Among the remaining 38 patients, after a median follow-up of 21.8 months (range, 2.7–30.7 months), the median progression-free survival (mPFS) was 6.9 months (95% CI, 4.7–9.1 months), and the 6-month PFS rate stood at 60.5%. Analysis based on the histologic subgroups of RLPS revealed comparable mPFS values (WDLPS vs DDLPS vs MLPS: 8.4 months vs 5.8 months vs not reached, respectively; p = 0.126; Figure 2(a)). In addition, the mPFS among FNCLCC grade subgroups was 6.9 months (95% CI, 4.6–9.2 months) with G1, 7.4 months (95% CI, 0–15.3 months) with G2, and 5.8 months (95% CI, 3.5–8.1 months) with G3 (p = 0.086; Figure 2(b)).

Figure 2.

Kaplan–Meier curve of subgroup analysis of PFS in 38 RLPS patients who underwent combination therapy of eribulin plus anlotinib and camrelizumab. (a) PFS in subgroups of WDLPS (blue line), DDLPS (red line), and MLPS (green line) was compared, showing that the mPFS between the histologic subtypes of RLPS was no significant difference (WDLPS vs DDLPS vs MLPS: 8.4 months vs 5.8 months vs not reached, respectively; p = 0.126). (b) PFS in G1 (blue line), G2 (red line), and G3 (green line) RLPS were compared, and the mPFS between the different FNCLCC grade subgroups showed no significant differences (G1 vs G2 vs G3: 6.9 months vs 7.4 months vs 5.8 months, respectively; p = 0.086).

One among the eight patients who showed a PR underwent surgery before experiencing disease progression. The remaining seven patients had a mPFS of 9.2 months (95% CI, 7.0–11.3 months). Six of these patients exhibited tumor progression, with PFS durations ranging from 7.4 to 21.9 months. After completing 21 cycles of combination therapy, 1 patient maintaining a PR status discontinued eribulin treatment due to TRAEs but continued maintenance therapy with anlotinib and camrelizumab (Figure 3).

Figure 3.

One patient with MLPS achieved partial response after a combination therapy of eribulin plus anlotinib and camrelizumab. (a) The baseline MLPS (blue arrow) in the retroperitoneal space, and (b) the patient maintained a partial response (blue arrow) after 21 cycles of combination treatment.

Before disease progression, six patients underwent surgery, resulting in complete resection (R0/R1) for five of them. Pathological analysis revealed a pCR in one patient with MLPS and an 80% response rate in another with DDLPS. The patient achieving pCR underwent 7.5 cycles of combination therapy and attained PR according to RECIST v1.1. Furthermore, 10 patients underwent surgery post-disease progression due to severe symptoms or emergency conditions. Among them, seven had R0/R1 resections. However, locoregional recurrence occurred in 6 out of 12 patients with R0/R1 resection.

Currently, four patients continue to receive combination therapy. A total of 20 patients have passed away, with 3 of them due to COVID-19 infection. The median survival (mOS) has not yet been reached.

Univariate and multivariate Cox regression analyses

Univariate and multivariate Cox regression analyses were conducted to explore the association between PFS and the patient’s clinical characteristics in this study (Table 5). The results of the univariable analysis indicated that ECOG PS, stage, and TRAE grade significantly affected PFS as prognostic factors. In the multivariate analysis, ECOG PS emerged as an independent risk factor for PFS (HR = 3.66, 95% CI, 1.31–10.20, p = 0.013).

Table 5.

Univariate and multivariate Cox regression analyses of the relationship between clinicopathological parameters and PFS.

Variable	N (%)	mPFS (months, 95% CI)	Univariable		Multivariable
Variable	N (%)	mPFS (months, 95% CI)	HR (95% CI)	p value	HR (95% CI)	p value
Gender
Female	21 (55.3)	8.33 (6.3–NA)	Reference
Male	17 (44.7)	5.80 (4.2–NA)	1.41 (0.69–2.88)	0.348
Age
<60	28 (73.7)	7.38 (5.13–15)	Reference
⩾60	10 (26.3)	6.52 (2.67–NA)	1.27 (0.56–2.85)	0.570
ECOG PS
0	13 (34.2)	19.27 (6.73–NA)	Reference		Reference
1–2	25 (65.8)	5.80 (4.2–8.33)	4.5 (4.7–12)	0.003	3.66 (1.31–10.20)	0.013
Lines of treatment
First	30 (78.9)	7.16 (5.80–15)	Reference
Second	8 (21.1)	5.37 (2.97–NA)	1.36 (0.58–3.20)	0.480
Eribulin dose
<1.1	15 (39.5)	6.93 (4.20–NA)	Reference
⩾1.1	23 (60.5)	7.83 (5.13–19.3)	0.81 (0.39–1.69)	0.571
Stage
Metastatic	7 (18.4)	5.13 (0.61–9.65)	Reference		Reference
Locally advanced	31 (81.6)	8.33 (6.42–10.24)	0.28 (0.11–0.72)	0.008	0.40 (0.15–1.04)	0.060
Grades of TRAEs
<3	22 (57.9)	6.30 (4.20–8.33)	Reference		Reference
⩾3	16 (42.1)	9.17 (4.20–NA)	0.40 (0.18–0.89)	0.025	0.67 (0.28–1.56)	0.349

In univariable Cox regression analysis, those with ECOG PS of 0 had a significantly longer PFS compared to those with ECOG PS of 1–2 (HR = 4.5, 95% CI, 4.7–12, p = 0.003); those with 3 or higher grades of TRAEs had a significantly longer PFS than those with 1–2 grades of TRAEs (HR = 0.4, 95% CI, 0.18–0.89, p = 0.025); those with locally advanced RLPS had a longer PFS than those with metastatic RLPS (HR = 0.28, 95% CI, 0.11–0.72, p = 0.008). In multivariate Cox regression analysis, ECOG PS was the independent risk factor of PFS.

CI, conference interval; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; mPFS, median progression-free survival; PFS, progression-free survival; RLPS, retroperitoneal liposarcoma; TRAEs, treatment-related adverse events.

Discussion

This retrospective study reported a cohort of 47 RLPS patients who received combination therapy of eribulin, anlotinib, and camrelizumab. This cohort study revealed the efficacy of this combination therapy for RLPS, with an ORR of 18.2% based on RECIST v1.1, a mPFS of 6.93 months, and a 6-month PFS rate of 60.5%. The ORR in patients with MLPS was higher than those with DDLPS and WDLPS (50% vs 17.9% vs 0%, respectively). In addition, the mPFS for the patients with WDLPS, DDLPS, and MLPS was 8.4 (95% CI, 4.1–12.7) months, 5.8 (95% CI, 3.3–8.3) months, and not reached, respectively. The study emphasized both the treatment safety profile and the patient’s tolerance to TRAEs. Moreover, the minimal loss to follow-up validated the data’s reliability.

When compared to standard chemotherapy regimens such as anthracyclines, ifosfamide, and their combinations,^12,34 our observed ORR and PFS displayed substantial improvements. In addition, our findings outperformed the outcomes reported for single-agent eribulin in the advanced LPS study, where the ORR was notably lower, and the mPFS was at 2.9 months.¹⁶ A previous retrospective study on anlotinib and camrelizumab combined therapy showed an ORR of 13.3% in RLPS cases,²⁹ notably lower than our study combining these with eribulin. However, the ORRs of different histological subtypes were similar between the two studies, with WDLPS and MLPS at 0 and 50%, and DDLPS at 17.9% and 21.4%, respectively.²⁹ In addition, our study’s results may be more reliable due to a higher sample size.

One particularly notable case in our study involved a patient diagnosed with MLPS, achieving a PR status after completing 7.5 treatment cycles and subsequently undergoing complete resection with confirmed pCR upon pathological analysis. In our study, MLPS patients exhibited an ORR of 50%, and the mPFS remained undefined after a median follow-up of 21.8 months. These findings underscored the remarkable efficacy of our treatment regimen for MLPS, a subtype recognized for its chemotherapeutic responsiveness. Several retrospective single-center studies have reported ORRs ranging from 43.2% to 48% with doxorubicin-based conventional chemotherapy in MLPS patients based on RECIST criteria.^12,35,36 In addition, another retrospective study demonstrated an ORR of 51% with trabectedin,³⁷ a marine-derived alkaloid known for its multifaceted mechanisms affecting critical cellular processes within tumor cells and the tumor microenvironment.^38,39 Our study highlights the effectiveness of combination therapy for MLPS. Nonetheless, larger prospective studies with more patient cohorts are required to validate these findings, particularly to explore potential survival benefits.

In our study, we analyzed to assess efficacy and safety across different eribulin dose intensities. Patients were divided into two groups: high dose (1.1–1.4 mg/m²) and low dose (0.7–1.1 mg/m²). The ORRs were 24.0% for the high-dose group and 10.5% for the low-dose group. Despite the higher ORR in the high-dose group, no statistically significant difference was observed (p = 0.433). Similarly, the DCRs were 72.0% and 78.9% for high-dose and low-dose groups, respectively, without a statistically significant difference (p = 0.731). For the safety analysis, 22 (78.6%) patients experienced TRAEs, with 14 (50.0%) in the high-dose group encountering grade 3 or higher TRAEs, compared to 14 (73.7%) patients and 7 (36.8%) with TRAEs and grade 3 or higher TRAEs, respectively, in the low-dose group. No significant differences were observed in the incidence rates of any TRAEs or grade 3 and higher TRAEs between the two groups (p = 0.737 and p = 0.551, respectively). Univariant Cox regression analysis revealed a trend toward longer mPFS in the high-dose group compared to the low-dose group, but this difference was not statistically significant (HR = 0.81, 95% CI, 0.39–1.69, p = 0.571). These findings suggest that our study’s high-dose group demonstrated a slightly higher ORR compared to the LEADER study (24% vs 22%),¹⁷ implying that a moderate increase in eribulin dosage might enhance therapeutic efficacy.

We further conducted a comparative analysis between two treatment regimens implemented at our center: TKI plus ICI and combination chemotherapy with TKI and ICI.²⁹ The observed TRAEs in our study markedly differed from those in the TKI plus ICI study. TRAEs, primarily attributed to chemotherapy, were more prevalent, including neutropenia (53.2%), anorexia (21.3%), and fatigue (19.1%), among others. Notably, chemotherapy-induced myelosuppression is a well-known and potentially fatal side effect of cancer treatment,⁴⁰ aligning with our findings. Intriguingly, the combination therapy involving chemotherapy had a lower incidence of hypertension compared to the other group (8.5% vs 24.6%), indicating a significant statistical difference (p = 0.031).

Furthermore, TRAEs associated with the endocrine system were significantly lower in the chemotherapy combination, although statistical significance was not achieved (12.8% vs 26.3%, p = 0.087). Thus, our findings suggest that combining chemotherapy with ICI and TKI might provide a safer treatment approach for RLPS patients by mitigating the risk of adverse events from TKI or ICI. However, the limited number of relevant trials impeded a comprehensive understanding. A meta-analysis of randomized controlled trials evaluating first-line treatment options for advanced non-small-cell lung cancer revealed that most irAEs with a PD-1/PD-L1 inhibitor plus chemotherapy were less prevalent compared to a PD-1/PD-L1 inhibitor alone.⁴¹ The immunosuppressive effects of chemotherapy might contribute to a reduced rate of irAEs,^41,42 although further elucidation of this mechanism requires additional data for validation.

In this study, several notable limitations merit consideration. First, it is essential to recognize that while ORR and PFS were explored as significant outcomes impacting treatment decisions, OS stands as the gold-standard endpoint in oncology studies. Unfortunately, our study did not reach OS. Second, this study was retrospective and sourced its patient data from a single-center cohort, potentially limiting the generalizability of the findings. Third, most of the RLPS patients in the study were locally advanced, and metastatic patients were in the minority. Thus, the result of prognoses, such as PFS and OS, might be overestimated. Fourth, the duration of follow-up was insufficient to adequately evaluate the long-term prognosis. Despite these limitations, the observed effectiveness of these drugs in treating advanced or metastatic RLPS, compared to conventional treatments, is noteworthy.

Conclusion

In conclusion, the combination therapy involving eribulin, anlotinib, and camrelizumab demonstrated promising efficacy in RLPS patients, particularly those with MLPS. Regarding safety, patients typically tolerated the combination therapy well, experiencing manageable TRAEs.

Supplemental Material

sj-docx-1-tam-10.1177_17588359241276968 – Supplemental material for Advancing treatment efficacy: combined therapy of eribulin, anlotinib, and camrelizumab in advanced or metastatic retroperitoneal liposarcoma

Supplemental material, sj-docx-1-tam-10.1177_17588359241276968 for Advancing treatment efficacy: combined therapy of eribulin, anlotinib, and camrelizumab in advanced or metastatic retroperitoneal liposarcoma by Weiwei Jia, Jianhui Wu, Hongtao Zhang, Yan Wu, Daoning Liu, Zhen Wang, Xiaopeng Wang, Chengpeng Li and Chunyi Hao in Therapeutic Advances in Medical Oncology

Footnotes

Acknowledgements

The authors thank all of the colleagues who contributed to this study.

Declarations

ORCID iDs

Weiwei Jia

Chunyi Hao

Supplemental material

Supplemental material for this article is available online.

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