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Phase II Study of Eribulin plus Pembrolizumab in Metastatic Soft-tissue Sarcomas: Clinical Outcomes and Biological
Candace L Haddox1, Michael J Nathenson1, Emanuele Mazzola2
1Sarcoma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Purpose:
Eribulin modulates the tumor-immune microenvironment via cGAS-STING signaling in preclinical models. This non-randomized phase II trial evaluated the combination of eribulin and pembrolizumab in patients with soft-tissue sarcomas (STS).
Patients And Methods:
Patients enrolled in one of three cohorts: leiomyosarcoma (LMS), liposarcomas (LPS), or other STS that may benefit from PD-1 inhibitors, including undifferentiated pleomorphic sarcoma (UPS). Eribulin was administered at 1.4 mg/m2 i.v. (days 1 and 8) with fixed-dose pembrolizumab 200 mg i.v. (day 1) of each 21-day cycle, until progression, unacceptable toxicity, or completion of 2 years of treatment. The primary endpoint was the 12-week progression-free survival rate (PFS-12) in each cohort. Secondary endpoints included the objective response rate, median PFS, safety profile, and overall survival (OS). Pretreatment and on-treatment blood specimens were evaluated in patients who achieved durable disease control (DDC) or progression within 12 weeks [early progression (EP)]. Multiplexed immunofluorescence was performed on archival LPS samples from patients with DDC or EP.
Results:
Fifty-seven patients enrolled (LMS, n = 19; LPS, n = 20; UPS/Other, n = 18). The PFS-12 was 36.8% (90% confidence interval: 22.5-60.4) for LMS, 69.6% (54.5-89.0) for LPS, and 52.6% (36.8-75.3) for UPS/Other cohorts. All 3 patients in the UPS/Other cohort with angiosarcoma achieved RECIST responses. Toxicity was manageable. Higher IFNα and IL4 serum levels were associated with clinical benefit. Immune aggregates expressing PD-1 and PD-L1 were observed in a patient that completed 2 years of treatment.
Conclusions:
The combination of eribulin and pembrolizumab demonstrated promising activity in LPS and angiosarcoma.
Insights
The combination of eribulin and pembrolizumab showed promising results in treating soft-tissue sarcomas, particularly liposarcomas and angiosarcomas. This trial evaluated the drug combination
Area of Science:
- Oncology
- Immunotherapy
- Pharmacology
Background:
- Eribulin is known to modulate the tumor-immune microenvironment through cGAS-STING signaling.
- Soft-tissue sarcomas (STS) are a heterogeneous group of cancers with varying responses to immunotherapy.
- Combining chemotherapy with immune checkpoint inhibitors is a strategy to enhance anti-tumor activity.
Purpose of the Study:
- To evaluate the efficacy and safety of combining eribulin and pembrolizumab in patients with STS.
- To assess the 12-week progression-free survival (PFS-12) rate in specific STS subtypes: leiomyosarcoma (LMS), liposarcoma (LPS), and other STS (including undifferentiated pleomorphic sarcoma, UPS).
- To explore the relationship between immune biomarkers and clinical response.
Main Methods:
- A non-randomized phase II clinical trial involving 57 patients with STS across three cohorts (LMS, LPS, UPS/Other).
- Patients received eribulin (1.4 mg/m2 IV on days 1 and 8) combined with pembrolizumab (200 mg IV on day 1) every 21 days.
- Primary endpoint was PFS-12; secondary endpoints included objective response rate, median PFS, overall survival (OS), and safety. Immune markers (IFNα, IL4, PD-1, PD-L1) were analyzed.
Main Results:
- PFS-12 rates were 36.8% for LMS, 69.6% for LPS, and 52.6% for UPS/Other.
- All three angiosarcoma patients within the UPS/Other cohort achieved RECIST responses.
- Higher serum levels of IFNα and IL4 correlated with clinical benefit; manageable toxicity was observed.
Conclusions:
- The combination of eribulin and pembrolizumab demonstrated promising clinical activity, especially in liposarcomas and angiosarcomas.
- The observed immune modulation suggests a potential synergistic effect between eribulin and pembrolizumab.
- Further investigation into this combination therapy for specific STS subtypes is warranted.
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