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

Abstract

Purpose: E7389-LF is a liposomal formulation of eribulin that contributes to tumor vascular remodeling. The phase II part of this phase Ib/II study assessed the efficacy/safety of E7389-LF in combination with nivolumab in several disease cohorts; herein, we report results from the small cell lung cancer (SCLC) cohort.

Experimental design: Patients with unresectable/measurable SCLC and disease progression with first-line platinum-based chemotherapy with/without an immune checkpoint inhibitor (ICI) were enrolled to receive E7389-LF 2.1 mg/m2 plus nivolumab 360 mg intravenously every 3 weeks. The primary objective of this part was to assess the objective response rate (ORR). Secondary objectives included assessments of safety and progression-free survival (PFS); exploratory assessments included overall survival (OS) and biomarkers.

Results: Thirty-four patients were enrolled. By the data cut-off date (May 31, 2022), 29 (85.3%) had discontinued. Efficacy/biomarker analyses included 33 patients (1 had their diagnosis changed postenrollment); the ORR of E7389-LF plus nivolumab was 24.2% [95% confidence interval (CI): 11.1-42.3], the median PFS was 3.98 months (95% CI: 2.63-4.40), and, at a median follow-up of 10.6 months, the median OS was not reached (95% CI: not estimable). Notably, 27 of 33 patients (81.8%) had received an ICI as their prior first-line therapy. Treatment-related, treatment-emergent adverse events occurred in 97.1% (any grade) and 82.4% (grade ≥3) of enrolled patients; the most common event was neutropenia. Changes in vascular and immune-related plasma markers were observed.

Conclusions: E7389-LF 2.1 mg/m2 in combination with nivolumab 360 mg every 3 weeks showed notable antitumor activity as second-line therapy for SCLC; no new safety signals were observed compared with either agent as monotherapy.

Significance: This phase II part of a phase Ib/II study assessed liposomal eribulin (E7389-LF) plus nivolumab in 34 patients with pretreated SCLC; 8 of 33 evaluable patients (including 6/27 pretreated with ICIs) had objective responses. The combination was tolerable; increases in vasculature-related biomarkers tended to correlate with responses.

FIGURE 1

Percentage changes in sums of diameters of target lesions from baseline over time (A)^a, and by PD-L1 CPS at nadir in all patients (B), patients with a biopsy (C), and patients with an archival tumor sample (D) ^aPatients could continue to receive study drugs beyond disease progression if they had investigator-assessed clinical benefit and were tolerating study drugs. A includes data from beyond disease progression. CPS, combined positive score; ICI, immune checkpoint inhibitor; N/A, not available; PD-L1, programmed cell death ligand 1.

FIGURE 2

Kaplan–Meier Curves of PFS (A) and OS (B). CI, confidence interval; OS, overall survival; PFS, progression-free survival.

FIGURE 3

Swimmer plots of patients by course of treatment and dose reduction of E7389-LF (A) and lines of subsequent therapies received during survival follow-up (B). Patients could continue to receive study drugs beyond disease progression if they had investigator-assessed clinical benefit and were tolerating study drugs. This figure includes data from beyond disease progression. #L, line of treatment number; AE, adverse event; BSC, best supportive care; PD, progressive disease; PR, partial response.

FIGURE 4

Changes from baseline in select vasculature and IFN-related biomarkers weekly to C3D1 (A), per cycle to C8D1 (B), by tumor response (for vasculature-related biomarkers; C), and by presence of prior ICI treatment (for IFN-related biomarkers; D). Lines represent medians; error bars represent 95% CI. For box-and-whisker plots in C, the horizontal line represents the median, the box represents the interquartile range, the whiskers represent the largest or smallest values within 1.5 times the interquartile range (either above the 75th percentile or below the 25th percentile), and diamonds represent outliers. P values are: *, P < 0.05; **, P < 0.01; ***, P < 0.001; patient numbers are as follows: A: n = 33 (C1D1, C1D8), n = 32 (C1D15), n = 30 (C2D1), n = 29 (C2D8), n = 28 (C2D15), n = 25 (C3D1). B: n = 33 (C1D1). n = 30 (C2D1), n = 25 (C3D1), n = 24 (C4D1), n = 19 (C5D1), n = 12 (C6D1), n = 8 (C7D1), n = 7 (C8D1). C: for CR/PR, n = 8 (C2D1, C3D1, C4D1); for non-CR/PR, n = 22 (C2D1), n = 17 (C3D1), n = 16 (C4D1). D: for prior ICI, n = 27 (C1D1, C1D8), n = 26 (C1D15), n = 25 (C2D1, C2D8, C2D15), n = 20 (C3D1); for no prior ICI, n = 6 (C1D1, C1D8, C1D15), n = 5 (C2D1), n = 4 (C2D8), n = 3 (C2D15), n = 5 (C3D1). C#D#, cycle #, day; CR, complete response; ICI, immune checkpoint inhibitor; IFNγ, interferon gamma; IP-10, IFN gamma-induced protein 10; MIG, monokine induced by gamma IFN; PECAM1, platelet endothelial cell adhesion molecule 1; PR, partial response; TEK, TEK receptor tyrosine kinase; TIE2, tyrosine kinase immunoglobulin and EGF homology domains 2.