Fecal microbiota transplantation plus immune checkpoint inhibitor rechallenges in patients with advanced non-small cell lung cancer: a single-arm exploratory study.

Background: The management of advanced non-small cell lung cancer (NSCLC) after progression on initial immunotherapy represents a significant clinical challenge. Immune checkpoint inhibitor (ICI) rechallenge is a considered option, yet its efficacy remains limited. Strategies to enhance the efficacy of ICI rechallenge are urgently needed. There is a pressing need for novel strategies to sensitize tumors to ICI rechallenge. Previous studies have established a correlation between the gut microbiota and the tumor response to immunotherapy, and have explored the application of fecal microbiota transplantation (FMT) in modifying the immune response by restoring the gut microbiota. However, the potential of FMT from healthy donor to reverse immunotherapy resistance in patients with NSCLC has not been previously investigated. This preliminary study aimed to provide initial insights into the safety, tolerability, and potential efficacy of the combined therapy of FMT from healthy donor with immunotherapy rechallenge in NSCLC patients. Methods: In this single-arm exploratory study, patients with advanced NSCLC who progressed after prior immunotherapy were screened and enrolled based on predefined eligibility criteria, including prior response to ICIs and adequate organ function. Eligible patients received oral FMT capsules from healthy donors followed by rechallenge with camrelizumab. The primary endpoint was safety and feasibility [incidence of adverse events (AEs) graded by CTCAE v5.0]. Secondary end points included the objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Fecal and blood samples were collected for exploratory analyses of microbiota, metabolome, and T cell receptor (TCR) repertoire. Results: Seven patients (all male, median age 55 years) were enrolled and constituted the analysis population. The majority (5/7) had received three or more prior lines of therapy. During the follow-up period, none experienced grade 4 or higher AEs. The treatment-related AEs were mainly associated with immunotherapy, and only grade 1 FMT-related AEs (e.g., nausea, diarrhea, bloating, and constipation) were reported. One patient achieved a partial response (PR) and one achieved stable disease (SD) with PFS times of 14.6 and 8.1 months, respectively. The median PFS was 1.5 months [95% confidence interval (CI): 1.24-1.75], and the OS was 12.1 months (95% CI: 0.3-23.9) for all patients. Moreover, the treatment modulated the composition of the intestinal flora in all patients, with alpha diversity increasing in responders and decreasing in non-responders. Conclusions: The results indicated that the combined therapy of FMT and immunotherapy rechallenge was feasible and demonstrated a tolerable safety profile in this small cohort. The observed clinical activity is preliminary. These findings support the need for larger, controlled trials to assess the efficacy of this approach.