Microsatellite stable (MSS) metastatic colorectal cancer (mCRC) is one of the tumor type in which PD-1 inhibitor as monotherapy has proven less effective. Studies have shown that anti-VEGF therapies may enhance anti-PD-1 efficacy and microbiome-based therapies can overcome resistance to anti-PD-1. This study was to explore the efficacy and safety of fecal microbiota transplantation (FMT) combined with anti-VEGF and anti-PD-1 therapy in advanced mCRC with MSS.
This open-label, phase II trial (ChiCTR2100046768) was conducted at Renmin Hospital of Wuhan University. Patients with MSS mCRC progressed after at least 2-lines prior systemic treatments were administered custom-made fecal microbiota capsule (10#, 3 times per day, day1-3) plus fruquintinib (5-3mg; once per day, 2 weeks on/1 week off) and tislelizumab (200mg, day 4) every 3 weeks. Stool and peripheral blood were collected to detect the dynamic changes of intestinal microbiota diversity and immune metabolism indexes. The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety.
From May 10, 2021 to January 17, 2022, 20 patients were assigned to treatment. As of data cutoff on September 25, 2022, with a median follow-up time of 10.7 months (IQR 7.9-13.7), median PFS was 9.6 months (95% CI 6.8-12.5) and median OS was 13.5 months (95% CI 9.0-NR). The median treatment duration was 7 cycles. A reduction in the size of target lesions was achieved by 60% (12/20). ORR was 20% (4/20; 95%CI, 6.6-44.3). DCR was 95% (19/20; 95%CI, 73.1-99.7). Quality of life (QoL) improved in 55% of patients. The most common treatment-related adverse events of grade 3 or worse were stool occult blood positive (15%), hand-foot skin reaction (10%), proteinuria (10%), increased ALT (5%), hypertension (10%), hypothyroidism (5%). No treatment-related deaths occurred.
Ttislelizumab combined with fruquintinib and FMT significantly improved PFS and OS in advanced MSS mCRC compared with historical controls, with a manageable safety profile and good QoL. It deserves to be validated in a larger trial.
ChiCTR2100046768, 2021-5-28.
The authors.
National Natural Science Foundation of China (grant no.82102954) Central Leading Local Science and Technology Development Special Foundation (grant no. ZYYD2020000169).
All authors have declared no conflicts of interest.