A phase 2 study to assess the safety and efficacy of FLX475 (tivumecirnon) combined with pembrolizumab in patients with advanced or metastatic gastric cancer.
Authors: Oh Do-Youn , Ryu Min-Hee , Hwang Jun-Eul , Cho Jaeyong , Zang Dae Young , Oh Sang Cheul , Lee Jeeyun , Lee Keun-Wook , Rha Sun Young , Shim Byoung Yong , Ho William , Chisamore Michael Jon , Rhee Paul Dong , Jung Sooa , Kim Taewan , Yoon Jiyeon , Jang Hosung , Baek Eunhye , Noh Young Su 
Published: January 2025

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Background:
Regulatory T-cells (T
regs
) suppress anti-tumor immunity by migrating into tumors via CCL17/CCL22 chemokines binding to CCR4. FLX475 (tivumecirnon), a selective CCR4 antagonist, inhibits T
reg
recruitment, enhancing the effector T-cell (T
eff
) response in the tumor microenvironment. Preclinical studies demonstrate that FLX475 increases the T
eff
/T
reg
ratio and boosts anti-tumor efficacy, both as monotherapy and in combination with checkpoint inhibitors (CPI). Here, we present findings on the safety and efficacy of FLX475 with pembrolizumab in a Phase 2 trial, aimed at improving therapeutic outcomes in advanced or metastatic gastric cancer (GC) patients.
Methods:
This Phase 2, open-label study (NCT04768686) assesses the safety and efficacy of FLX475 combined with pembrolizumab in advanced or metastatic GC patients. Patients received FLX475 100 mg PO QD and pembrolizumab 200 mg IV Q3W. Cohort 1 included CPI-naïve Epstein-Barr Virus (EBV)-negative GC patients who had progressed on at least two prior treatments. Cohort 2 included CPI-naïve EBV-positive GC patients who had received at least one prior treatment. Both cohorts were selected based on high CCR4 ligand expression and T
reg
enrichment, expected to enhance treatment response. The primary objective of the study was to assess the anti-tumor efficacy of the study treatment, as assessed by the investigator using RECIST 1.1.
Results:
A total of 20 patients were enrolled in the study, with 10 patients in each cohort. The combination of FLX475 and pembrolizumab was well-tolerated across both cohorts. The most common treatment-related adverse events occurred in more than 10% of patients across cohorts were QTc prolongation (35.0%), and pruritus (15.0%), which were manageable and consistent with the known profiles of the individual agents. In Cohort 2, the confirmed objective response rate (ORR) was 60.0% (95% CI: 26.2 to 87.8). The median time to response (mTTR) was 2.7 months, with a median duration of response (mDOR) of 17.3 months. The median progression-free survival (mPFS) for this cohort was 10.4 months, while the median overall survival was not reached. In Cohort 1, no objective responses were observed, and the best response achieved was stable disease. The relationship between treatment outcomes and biomarkers including CCR4 expression levels and the T
eff
:T
reg
ratio was confirmed in exploratory analyses.
Conclusions:
The combination of FLX475 with pembrolizumab was well-tolerated and showed promising anti-tumor activity and durable responses in patients with advanced or metastatic EBV-positive GC.
Clinical trial information: NCT04768686
.

Cohort 1 (EBV (-) GC)N=10
Cohort 2 (EBV (+) GC)N=10

ORR
n (%)(95% CI)
0 (0.0)(-)
6 (60.0)(26.2, 87.8)

mTTR
Months (95% CI)
-
2.7 (1.2, -)

mDOR
Months (95% CI)
-
17.3 (2.7, -)

mPFS
Months (95% CI)
1.4 (1.1, 1.5)
10.4 (1.0, -)