2646 Background: Immunotherapy(IT) combined with chemotherapy has gradually emerged as the first-line(1L) standard treatment for most advanced tumors; however, numerous studies have demonstrated that chemo-immunotherapy can lead to a reduction in intestinal microbiota diversity, subsequently resulting in compromised immunity. So we assumed whether supplement gut microbiota through fecal microbiota transplantation (FMT) and subsequent anti-PD-(L)1 inhibitor therapy as maintenance therapy could potentially prolong progression-free survival (PFS) in patients(pts) with advanced gastric and non small cell lung cancers (ChiCTR2100054928). Methods: This is a prospective, single-arm exploratory study. The key inclusion criteria encompassed pts with unresectable advanced gastric/gastroesophageal union carcinoma (GC) and advanced non small cell lung cancer (NSCLC), who demonstrated partial response(PR) or stable disease (SD) after 1L therapy with ECOG scores ranged from 0 to 1.There were 2 FMT healthy donors, FMT was performed via nasoenteric tubes or oral capsules after 1L therapy, followed by maintenance therapy with anti-PD-(L)1 inhibitors until unacceptable toxicity or disease progression(PD). Results: From Jan. 2022 to Dec. 2023, a total of 17 pts were enrolled, including 9 GC and 8 NSCLC. 82% were male, and the median age was 68 years (range, 49-80). All pts achieved either a partial response (PR, n=7) or stable disease (SD, n=10) after 1L therapy and subsequently underwent FMT prior to commencing maintenance therapy. The intestinal microbiomes used for FMT with nasoenteric tubes were from the same donor (GC [n=3], NSCLC [n=5]), while those in the capsules were from a different donor (GC [n=6], NSCLC [n=3]). We defined the time from receiving 1L therapy to FMT as PFS0; and from the FMT to PD as PFS1. The sum of PFS0 and PFS1 represents the time from the start of 1L therapy to PD as PFS. Of the 17 recipients, 12 showed SD (GC [n=6], NSCLC [n=6]) and 5 showed PD (GC [n=3], NSCLC [n=2]). In the GC group, median follow-up was 8.8 months (interquartile range [IQR] 5.1-9.7), with unreached median PFS1 and a one-year PFS rate of 78%. For NSCLC, median follow-up was 8.0 months (IQR 4.2-12.2), with unreached median PFS1 and a one-year PFS rate of 67%. No statistically significant differences were observed in pts who underwent FMT using two distinct methods. 53% of pts reported improved quality of life (QoL). 5 pts (29%) experienced grade 1-2 FMT-related toxicities, primarily gastrointestinal reactions, including diarrhea, gas, and abdominal pain, but no grade 3 or higher adverse events were identified. Conclusions: Administering FMT prior to 1L immune maintenance therapy in pts with advanced GC and NSCLC has the potential to prolong PFS, and demonstrate a favorable safety. However, these findings necessitate validation through larger-scale clinical trials. Clinical trial information: ChiCTR2100054928.