Phase I/II trial of healthy donor fecal microbiota transplant (hdFMT) in PD-1 relapsed/refractory (R/R) non-small cell lung cancer (NSCLC).

TPS8648 Background: A significant portion of patients (pts) with advanced NSCLC either do not respond or become refractory to immune checkpoint inhibitor (ICI) therapy administered alone or in combination with platinum chemotherapy. In addition to tumor-intrinsic mechanisms supporting resistance to anti-PD-1, the gut microbiome is a major tumor-extrinsic regulator of responses to anti-PD-1. In mice, gut microbiota modulate therapeutic activity of anti-PD-1 ICI, and administration of gut commensals or responder-derived fecal microbiota transplantation (R-FMT) promotes anti-PD-1 efficacy. Longitudinal analyses of gut microbiome samples from ICI-treated cancer pts suggests key bacterial species are associated with favorable response, although limited concordance among the identified species has been reported across studies. We and others have previously demonstrated that microbiome modulation reversed anti-PD-1 resistance in anti-PD-1 R/R melanoma, and augmented benefit of anti-PD-1 monotherapy in ICI-naïve melanoma. We hypothesize that intestinal dysbiosis mediates anti-PD-1 resistance in anti-PD-1 R/R NSCLC, and that hdFMT may resensitize NSCLC to PD-1 blockade. Methods: This is an investigator-initiated, phase II trial of hdFMT with pembrolizumab (P) in pts with R/R NSCLC progressed on prior anti-PD-1 based therapy alone or in combination with platinum chemotherapy. Pts must have measurable disease per RECIST v1.1, no untreated CNS metastases, and no contraindications to FMT administration. hdFMT is derived from non-obese, healthy, adults aged ≥18 to <70, with no chronic diseases, and no recent antibiotic exposure. Donors are screened broadly for transmissible agents including SARS-CoV-2 using bookend screening. hdFMT is processed to make fecal infusates and orally bioavailable capsules. Eligible pts receive P 200mg every 3 weeks (Q3W). hdFMT is administered endoscopically on D1, and D42, and thereafter via capsules until progression or unacceptable toxicity. Response is assessed at D73, and thereafter Q12W. Pts undergo tumor biopsies at baseline and at W8, with optional post-progression biopsy. Primary endpoint: overall response rate (ORR) assessed using RECIST v1.1 by Blinded Independent Central Review (BICR). Secondary endpoints include: safety, progression-free survival (PFS), overall survival (OS), and landmark PFS/OS. Key translational endpoints include immune activation (tumor tissue, blood), metagenomic engraftment, and transcriptomic analyses of intestinal luminal myeloid cells and exfoliome. The null hypothesis that the true ORR is 5% will be tested versus a 1-sided alternative hypothesis of ≥25%, using Simon’s minimax two-stage design (type I error 0.04, power 0.9, when true response rate is 0.25). PFS and OS will be estimated via Kaplan-Meier method. Enrollment has commenced. Clinical trial information: NCT05669846 .