Phase II Study of Eribulin plus Pembrolizumab in Metastatic Soft-tissue Sarcomas: Clinical Outcomes and Biological Correlates

Abstract

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.

Trial registration: ClinicalTrials.gov NCT03899805.

Figure 1.

Tumor response and survival. Best change from baseline scan (sum of longest tumor diameters, %) shown in waterfall plot (A). Duration on treatment shown in spider plot showing the change in sum of longest tumor diameters (%) compared with baseline scan across response assessments (B). The continuous lines in the spider plot represent the percent change in most relevant tumor measurement before progression (if any). The dashed lines represent the percent change in the most relevant tumor measurement after progression (if any). Kaplan–Meier curves of PFS (C) and OS (D). Asterisks (*) indicate UPS. CI, confidence interval; LMS, leiomyosarcoma; LPS, liposarcoma; mOS, median overall survival; mPFS, median progression free survival; PD, progressive disease; PR, partial response; SD, stable disease; UE, unevaluable; UPS, undifferentiated pleomorphic sarcoma.

Figure 2.

Serum cytokines and PBMC subsets in patients with DDC or EP. A, IFNα and IL4 serum levels in patients with DDC or EP at predose and C1D8. Wilcoxon rank-sum test P < 0.05. B, PBMC cell type abundance across individual cases from the liposarcoma cohort with DDC or EP. C, Peripheral CD4⁺ EM CD57⁺ cell abundance in patients with liposarcoma with DDC versus EP at predose and C1D8, adjusted P value of 0.035 and 0.099. D, C1D8 expression of IFNγ (top) and granzyme B (bottom) across immune subsets in cases from the liposarcoma cohort with DDC or EP, adjusted P value < 0.1 where shown. Key for C and D shown in lower left box. CM, central memory; EM, effector memory; MDSC, myeloid-derived suppressor cells; NK, natural killer; PMN, polymorphonuclear neutrophils; RA, CD45RA+; sen, senescent; Treg, regulatory T cells.

Figure 3.

Immune subsets and checkpoint expression in liposarcoma cases with DDC or EP. A, Heat map of CyCIF data from DDLPS samples with DDC or EP. Colors represent the Z scores of indicated cell counts, and dendrograms were generated by complete lineages using Euclidean distance matrix. B, PD-1+ and PD-L1+ cell counts in DDC and EP DDLPS samples. C, PD-1–PD-L1 interaction maps from case DDC6 and case EP2. The Spatial plots represent PD-1+ cells (green), PD-L1+ cells (red) and their interactions (black contour lines). The interaction was calculated by any given PD-1+ and PD-L1+ pairs within 20 um radius. The quantification is calculated by total number of PD-1–PD-L1 pairs divided by PD-1+ cells. D, PD-1+ neighborhood enrichment analysis. Bars represent the counts of each marker from cells within a 20um radius of any given PD-1+ cells, normalized by the total counts of each marker. The dotted line (ratio equal to 1) indicates no enrichment. E, Representative CyCIF images of PD-1+ neighborhoods from the case DDC6 and case EP2. Scale bar = 20 μm. F, Representative CyCIF image of immune checkpoint–expressing cell aggregates from case DDC6.