Background: Due to a lack of efficacy and long-term survival seen in previously-studied therapies, new therapies for pretreated advanced GC are warranted. E7389-LF is a new formulation that uses liposomes to encapsulate eribulin; this is anticipated to improve eribulin concentration in tumor tissues. E7389-LF and nivolumab have both shown efficacy as monotherapy in pretreated GC. E7389-LF may also synergize well with PD-1 inhibitors by acting as a cytotoxic therapy and by modulating the tumor microenvironment. Methods: Patients (pts) with unresectable and measurable GC, esophageal cancer, or small cell lung cancer who were previously treated with 1 (2 for GC) chemotherapy regimens were enrolled in the phase 2 part of Study 120 and treated with E7389-LF 2.1 mg/m² plus nivolumab 360 mg every 3 weeks (Q3W). In the GC cohort, pts had to show disease progression from combination therapy including a platinum drug + fluoropyrimidine (1^st-line therapy) and a taxane-containing regimen (2^nd-line therapy). The primary objective of the phase 2 part was to evaluate the objective response rate (ORR); secondary objectives included safety, progression-free survival (PFS), and pharmacokinetics. Other efficacy (including overall survival [OS]) and biomarker objectives were exploratory. Tumor responses were assessed by the investigators per RECIST v1.1. Results: 31 GC pts were included; median age was 63 years; 18 pts were male, 13 were female. By the data cutoff date (May 31, 2022), 29 pts discontinued (26 due to disease progression, 3 due to adverse events). 8 Pts had a partial response (PR); the ORR was 25.8% (95% CI 11.9–44.6). The median PFS was 2.69 months (95% CI 1.91–2.99). The median OS was 7.85 months (95% CI 4.47–not estimable). The 6-month OS rate was 61.3%; the 9-month OS rate was 44.7%. 30 Pts had ≥1 treatment-related TEAE, most commonly neutropenia (n = 24); 25 pts had at least 1 grade ≥3 treatment-related TEAE, most commonly neutropenia (n = 22). 16 Pts had ≥1 TEAE resulting in dose reduction of E7389-LF. 4 Pts had ≥1 TEAE resulting in withdrawal of E7389-LF or nivolumab, including asthma, cerebral hemorrhage, decreased appetite, pulmonary edema, and upper gastrointestinal hemorrhage (each n = 1). 29 Pts had an evaluable PD-L1 combined positive score (CPS); 5 of 20 pts (25.0%) with a CPS of < 5 and 2 of 9 (22.2%) with a CPS of ≥5 had a PR. Increases in pharmacodynamic markers including vasculature-related markers were observed; antitumor immunity was observed per changes in interferon gamma (IFNγ) and IFNγ-related markers. Conclusions: E7389-LF 2.1 mg/m² in combination with nivolumab 360 mg Q3W had promising efficacy for pretreated GC, as evidenced by the notable ORR of 25.8% as well as by PFS and OS. No new safety signals were identified for this combination. Biomarker changes suggested vascular remodeling activity and enhancement of antitumor immunity via IFNγ signaling. Clinical trial information: NCT04078295.