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. Patients and Methods: 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 (Q3W), E7389-LF 2.1 mg/m2 plus nivolumab 360 mg Q3W, E7389-LF 1.1 mg/m2 plus nivolumab 240 mg every 2 weeks (Q2W), or E7389-LF 1.4 mg/m2 plus nivolumab 240 mg Q2W. Primary objectives were to evaluate the safety/tolerability of each dose cohort and to determine the recommended phase 2 dose (RP2D). Secondary/exploratory objectives, including safety (dose-limiting toxicities [DLTs] and adverse events [AEs]), 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 Q3W [n=6], E7389-LF 2.1 mg/m2 Q3W [n=6], E7389-LF 1.1 mg/m2 Q2W [n=7], E7389-LF 1.4 mg/m2 Q2W [n=6]). Twenty-four patients were evaluated for DLTs, of whom 3 had DLTs (1 at E7389-LF 1.7 mg/m2 Q3W, 1 at 1.1 mg/m2 Q2W, and 1 at 1.4 mg/m2 Q2W). All patients had ≥1 treatment related treatment-emergent AE (TEAE); 68.0% had ≥1 grade 3-4 treatment-related TEAE. Changes in vasculature and interferon-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 studies was 2.1 mg/m2 plus nivolumab 360 mg Q3W.

Phase II Study of the Liposomal Formulation of Eribulin (E7389-LF) in Combination with Nivolumab: Results from the Small Cell Lung Cancer Cohort

“…No new safety signals were observed compared with the known profiles of each monotherapy ( 15, 16 ). The incidences of treatment-related leukopenia and neutropenia were similar to those in the phase Ib part of this study ( 10 ). Of note, more patients in this cohort (13/34 patients, 38.2%) received peg-GCSF than in the phase Ib part (4/25 patients, 16.0%; ref.…”

“…Study 120, an open-label phase Ib/II trial, was conducted to evaluate the potential of E7389-LF in combination with nivolumab in patients with various solid tumors. The phase Ib part evaluated the dosing and safety of E7389-LF + nivolumab in patients with solid tumors to determine a recommended phase II dose ( 10 ). The phase II part assessed efficacy and safety in cohorts of patients with gastric cancer, esophageal cancer, and SCLC.…”

Phase II Study of the Liposomal Formulation of Eribulin (E7389-LF) in Combination with Nivolumab: Results from the Gastric Cancer Cohort

“…In the phase Ib part of Study 120, the recommended phase II dose was E7389-LF 2.1 mg/m 2 (eribulin mesylate content) in combination with nivolumab 360 mg every 3 weeks, administered as intravenous infusions ( 9 ). E7389-LF could be dose-reduced in consecutive steps to 1.7, 1.1, and 0.8 mg/m 2 .…”

“…Immune phenotypes were assessed using methods modified from those previously used in the ABACUS trial ( 12, 13 ). Phenotypes were determined by a pathologist using a density proportion score (DPS) for panCK-CD8 ( 9 ). The DPS is based on the density of inflammatory cells within a tumor and can be used to score areas that range from those with minimal inflammatory cells to those with a higher percentage of inflammatory cells; scores were assessed in two compartments or “nests,” the tumor stroma and tumor epithelial nests.…”

“…In a phase I study of E7389-LF in patients with solid tumors, partial responses (PR) were observed in 10.3% of patients (six of 58), and no new or unexpected toxicities were observed compared with eribulin ( 8 ). It was determined that the pharmacokinetic profile of E7389-LF was superior to eribulin and that the dose of 2.0 mg/m 2 (as free eribulin) every 3 weeks should be considered for several types of solid tumors, including gastric cancer ( 9 ).…”