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374 Background: Pembrolizumab, anti–PD-1 antibody, provides response rates of around 15% in patients (pts) with PD-L1-positive advanced gastric cancer (AGC). Lenvatinib, a multikinase inhibitor of VEGF receptors and other receptor tyrosine kinases, substantially decreased the tumor-associated macrophages and increased infiltration of CD8-positive T cells and enhanced anti-tumor activity of PD-1 inhibitors in vivo model. This phase 2 study has been conducted to evaluate efficacy and safety of the combination of lenvatinib plus pembrolizumab in pts with AGC. Methods: Eligible pts were with AGC having measurable lesions according to RECIST ver. 1.1. Pts could be enrolled regardless of PD-L1 status. Pts received 20 mg oral lenvatinib daily plus 200 mg intravenous pembrolizumab every 3 weeks. Primary endpoint was objective response rate (ORR). Planned sample size was 29 pts based on Simon’s optimal two-stage design with one-sided ɑ = 5% and power = 80%. The threshold and expected ORRs were 10% and 30%. PD-L1 combined positive score (CPS) was assessed using the anti–PD-L1 22C3 antibody. Results: From October 2018 to March 2019, 29 pts (27 MSS and 2 MSI-H) were enrolled and assessed for anti-tumor response. Fourteen pts received the study treatment as first-line and 15 pts as second-line. ORR was 69% (95% CI 49 to 85). The disease control rate was 100%. ORR in MSS pts was 70%. ORR was numerically higher in pts with CPS≥1 (n=19, ORR 84%) than that of pts with CPS<1 (n = 10, ORR 40%). Median progression-free survival was 6.9 months (95% CI, 4.4-9.4 months) with 14 pts with ongoing treatment at the data cut off in August 2019. Grade ≥ 3 treatment related adverse events occurred in 13 pts (45%) including hypertension (34%), proteinuria (17%), and platelet count decreased (7%). Conclusions: Lenvatinib with pembrolizumab showed a promising antitumor activity with acceptable safety profiles for pts with AGC, which warrants further investigations in a larger cohort. Clinical trial information: NCT03609359 .

4044 Background: Regulatory T cells (Tregs) potentially induce the resistance of anti-PD1/PD-L1 inhibitors (A-PD1). TAS-116, a novel HSP90 inhibitor, enhanced antitumor immunity via reducing Tregs in vitro and in vivo. Combination of TAS-116 plus A-PD1 showed a superior tumor growth suppression compared with either treatment alone in vivo. Based on the above, we investigated safety and efficacy of TAS-116 in combination with nivolumab in patients with solid tumors. Methods: Enrolled patients received TAS-116 plus nivolumab in a dose-finding part to estimate the maximum tolerated dose and the recommended phase 2 dose (RP2D). Additional patients were enrolled in a dose-expansion part. TAS-116 monotherapy (orally once daily, 80mg on level 1, 120mg on level 2, and 160mg on level 3) was administrated for 2 weeks followed by the combination with nivolumab (intravenously every 2 weeks, 3 mg/kg). The primary endpoint was dose-limiting toxicities (DLTs) during the first cycle (4 weeks). PD-L1 combined positive score (CPS) and tumor mutation burden (TMB) were assessed. We also conducted biomarker research using paired samples from repeated tumor biopsies and blood collections. Results: A total of 44 patients with colorectal cancer (CRC, n = 29), gastric cancer (GC, n = 8), sarcoma (n = 5), non-small cell lung cancer (NSCLC, n = 1) and melanoma (n = 1) after standard of cares were enrolled. One patient had MSI-H CRC, but all other patients had MSS tumors. No DLTs were observed at all levels and TAS-116 160 mg was determined as RP2D. The common grade 3 or worse treatment-related adverse included AST/ALT increased (7%), creatinine increased (5%) and platelet count decreased (5%). Objective tumor response was observed in 6 patients including 4 MSS CRC, 1 MSI-H CRC and 1 sarcoma, resulting in objective response rate (ORR) of 16% in MSS CRC without prior A-PD-1. PD-L1 CPS and TMB could be evaluated in 18 and 17 MSS CRC without prior A-PD-1, respectively. ORR was 27% in patients with CPS ≥1 and 0% in patients with CPS < 1. ORR was 33% with TMB-high (median as the cut-off) and 12% with TMB-low. Analysis of tumor-infiltrating lymphocytes before treatment and after TAS-116 monotherapy demonstrated reduction of FoxP3hiCD45RA−Tregs fraction in the tumor microenvironment. Conclusions: The combination of TAS-116 160mg plus nivolumab had manageable safety profiles and anti-tumor activity especially for MSS CRC patients, which warrants further investigations in a large cohort. Clinical trial information: UMIN000032801 .

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