Phase Ib/II Study of a Liposomal Formulation of Eribulin (E7389-LF) plus Nivolumab in Patients with Advanced Solid Tumors: Results from Phase Ib

Abstract

Purpose: To determine a recommended dose of liposomal eribulin (E7389-LF) in combination with nivolumab in patients with advanced solid tumors, and to evaluate the safety, efficacy, pharmacokinetics, and biomarker impact of this regimen.

Experimental design: Japanese patients with advanced, nonresectable, or recurrent solid tumors and no existing alternative standard/effective therapy (except nivolumab monotherapy) were assigned to either E7389-LF 1.7 mg/m² plus nivolumab 360 mg every 3 weeks, E7389-LF 2.1 mg/m² plus nivolumab 360 mg every 3 weeks, E7389-LF 1.1 mg/m² plus nivolumab 240 mg every 2 weeks, or E7389-LF 1.4 mg/m² plus nivolumab 240 mg every 2 weeks. Primary objectives were to evaluate the safety/tolerability of each dose cohort and to determine the recommended phase II dose (RP2D). Secondary/exploratory objectives, including safety [dose-limiting toxicities (DLT) and adverse events (AE)], pharmacokinetics, efficacy [including objective response rate (ORR)], and biomarker results were used in determining the RP2D.

Results: Twenty-five patients were enrolled to treatment [E7389-LF 1.7 mg/mg² every 3 weeks (n = 6), E7389-LF 2.1 mg/m² every 3 weeks (n = 6), E7389-LF 1.1 mg/m² every 2 weeks (n = 7), E7389-LF 1.4 mg/m² every 2 weeks (n = 6)]. Twenty-four patients were evaluated for DLTs, of whom 3 had DLTs (1 at E7389-LF 1.7 mg/m² every 3 weeks, 1 at 1.1 mg/m² every 2 weeks, and 1 at 1.4 mg/m² every 2 weeks). All patients had ≥1 treatment-related treatment-emergent AE (TEAE); 68.0% had ≥1 grade 3-4 treatment-related TEAE. Changes in vasculature and IFN-related biomarkers were seen in each cohort. The overall ORR was 16%.

Conclusions: E7389-LF plus nivolumab was tolerable overall; the recommended dose for future study was 2.1 mg/m² plus nivolumab 360 mg every 3 weeks.

Significance: This phase Ib part of a phase Ib/II study assessed the tolerability and activity of a liposomal formulation of eribulin (E7389-LF) plus nivolumab in 25 patients with advanced solid tumors. The combination was tolerable overall; 4 patients had a partial response. Vasculature and immune-related biomarker levels increased, suggesting vascular remodeling.

FIGURE 1

Maximum percentage change from baseline in sums of tumor diameters and best overall response per RECIST v1.1. E7389-LF, eribulin liposomal formulation; PD, progressive disease; PR, partial response; Q#W, every # weeks; RECIST v1.1, Response Evaluation Criteria In Solid Tumors, version 1.1; SD, stable disease.

FIGURE 2

Percentage changes from baseline in sums of target lesion diameters over time per RECIST v1.1 by investigator assessment. Tumor types of patients with at least a 30% reduction at any timepoint are listed. ^aPlus nivolumab 360 mg every 3 weeks; ^bplus nivolumab 240 mg every 2 weeks. Q#W, every # weeks; RECIST v1.1, Response Evaluation Criteria In Solid Tumors version 1.1.

FIGURE 3

Analyses of changes in key biomarkers from baseline to C1D8 in all dosing cohorts (A) and from C1D1 to C2D1 in the E7389-LF 2.1 mg/m² every-3-weeks cohort (B). Boxes indicate the median and quartiles, the whiskers represent the largest or smallest values within 1.5 times the interquartile range, and * denotes an unadjusted P value of < 0.05 (Wilcoxon signed-rank test); the diamond shape ◊ denotes outlier. Biomarkers also known as: ^aTEK; ^bCXCL10. CXCL, C-X-C motif chemokine ligand; C#, cycle; D#, day #; IP10, IFNγ-induced protein 10; Q#W, every # week; TEK, TEK receptor tyrosine kinase; TIE2, tyrosine kinase immunoglobulin and EGF homology domains 2.