Phase II trial of transarterial chemoembolization followed by sintilimab (anti-PD-1), oxaliplatin, and S-1 combined with either trastuzumab (HER-2 positive) or apatinib (HER-2 negative) as first-line therapy for gastric cancer with liver metastases.

4050 Background: Liver metastases contribute to immunotherapeutic resistance and unfavorable outcomes. Transarterial chemoembolization (TACE) may alter the immune microenvironment and enhance immunotherapy efficacy. In this trial, we assessed the efficacy and safety of TACE followed by sintilimab (anti-PD-1), oxaliplatin and S-1 combined with either trastuzumab (HER-2 positive) or apatinib (HER-2 negative) in the treatment of gastric cancer with liver metastases (GCLM). Additionally, we explored gene mutations and the immune microenvironment between gastric cancer and its paired liver metastases. Methods: This single-center, single-arm, phase II trial enrolled 31 treatment-naive patients with GCLM. Patients received TACE for liver metastases, followed by sintilimab (200mg), oxaliplatin (130mg/m 2 ) and S-1 (40-60 mg bid for 14 days) every 3weeks combined with either trastuzumab (HER-2 positive, 8 mg/kg then 6 mg/kg, q3w) or apatinib (HER-2 negative, 250mg qd) until disease progression or intolerable toxicities. Tissue samples from gastric cancer and liver metastases were collected before treatment for DNA and RNA detection. The primary endpoints were PFS and ORR. The secondary endpoints were DCR, OS, and safety. Results: A total of 31 patients were enrolled, median 63 (41-76) years old, 27 male, 26 multiple liver metastases and all adenocarcinoma. Of them, 10 (32.3%) were HER2 IHC 3+, 7 (22.6%) HER2 IHC 2+/FISH+. Patients with PD-L1 CPS≥5, < 1 accounted for 19.4%, 51.6% respectively. With the median follow-up time of 396 days, the patients received a median of 6 treatment cycles. As of January 25, 2025, 27 patients were included in the efficacy and safety analyses. The ORR was 74.1%, with 5 CR, 15 PR, 3 SD, and 4 PD. DCR was 85.2%. The median PFS was 12 months, and the median OS was not reached. One- and two-year PFS rates were 51.6 and 27.1 %, respectively. One- and two-year OS rates were 89.1 and 74.0 %, respectively. Grade 3/4 treatment-related adverse events occurred in 18.5% of the patients, notably neutropenia, neurotoxicity and thyroid and liver dysfunctions. Forty-four unique mutated genes were identified in gastric cancer, which were involved in PI3K-Akt and drug resistance pathways. In its paired liver metastases, 59 specific mutated genes associated with MMR and cell cycle were identified. Liver metastases had more macrophages and CD8+ T cells, whereas NK and CD4+ memory resting cells were fewer than those in paired gastric cancer. Conclusions: TACE followed by sintilimab, oxaliplatin and S-1 combined with either trastuzumab or apatinib demonstrated promising efficacy and manageable safety as first-line therapy for GCLM. Gastric cancer and its paired liver metastases exhibited distinct gene mutations and immune microenvironment. Clinical trial information: ChiCTR2200057726 .