Discussion
tumor, DLTs, neutropenia, leukopenia, toxicity, tumors, cholangiocarcinoma
TUMOR, INFILTRATION, NEUTROPENIA, LEUKOPENIA, SOLID TUMORS, BONE MARROW SUPPRESSION, CPS, TUMORS, CHOLANGIOCARCINOMA
E7389-LF plus nivolumab was tolerable in patients with advanced solid tumors, with antitumor effects seen in both the every-3-weeks and every-2-weeks schedules. DLTs occurred in 3 patients, and all were resolved. All patients had at least one treatment-related TEAE, most commonly leukopenia and neutropenia, that were related to E7389-LF specifically. There were no substantial changes in the overall pharmacokinetic profiles of E7389-LF and nivolumab compared with previous clinical studies of E7389-LF (Incidence of leukopenia and neutropenia, as well as the occurrence of the neutrophil count nadir (caused by bone marrow suppression) around days 8 to 15 for the combination of E7389-LF plus nivolumab across dose schedules was consistent with studies of E7389-LF monotherapy (While care should be taken in drawing comparisons between clinical trials, the toxicity profile of the E7389-LF plus nivolumab combination appears comparable with that of E7389-LF alone (Clear changes in expression of collagen IV, TIE2, IFNγ, and IP10 from baseline suggests that E7389-LF plus nivolumab treatment results in vascular remodeling activity and enhancement of antitumor immunity via IFNγ signaling. Vasculature marker changes may be due to E7389-LF while changes in IFN-related biomarkers may be a result of ICI-combination therapy. The observed changes in immune phenotype from desert or excluded to inflamed suggest that E7389-LF might enhance immune activity in immune-insufficient types of tumors via a vascular remodeling effect, leading to passage of tumor-infiltrating lymphocytes into tumors. Of 2 patients with cholangiocarcinoma assessed, the patient who had their phenotype changed to “immune-inflamed” had a partial response; this was despite a very low tumor infiltration (PD-L1 CPS of 0) at baseline. Similarly, a preclinical study of E7389-LF and an anti-PD-1 therapy has suggested that E7389-LF shows unique immunomodulatory properties, including increasing the population of T cells and natural killer cells (As the results from this phase Ib analysis demonstrated promising antitumor activity with no new or unexpected safety signals, the phase II data are expected to shed further light on the potential success of E7389-LF plus nivolumab in the treatment of patients with solid tumors.