Regorafenib plus toripalimab in patients with metastatic colorectal cancer: a phase Ib/II clinical trial and gut microbiome analysisOriginal paper
Karen Pendergrass is a microbiome researcher specializing in microbiome-targeted interventions (MBTIs). She systematically analyzes scientific literature to identify microbial patterns, develop hypotheses, and validate interventions. As the founder of the Microbiome Signatures Database, she bridges microbiome research with clinical practice. In 2012, based on her own investigative research, she became the first documented case of FMT for Celiac Disease, four years before the first published case study.
Read MoreWhat was studied?
This phase Ib/II trial tested regorafenib, a multi-kinase inhibitor, combined with toripalimab, an anti-PD-1 antibody, in refractory metastatic colorectal cancer. It measured tolerability, response, survival, and a gut microbiome biomarker. The dose-escalation phase set a recommended dose of 80 mg regorafenib plus toripalimab. The expansion phase then measured objective response rate. Baseline fecal samples underwent 16S rRNA sequencing to link gut bacteria with treatment response and progression-free survival.
Who was studied?
Forty-two Chinese adults with metastatic, microsatellite-stable or MSI-low, mismatch-repair-proficient colorectal adenocarcinoma were enrolled. All had received at least 2 prior chemotherapy lines and were refractory to fluorouracil, oxaliplatin, and irinotecan. Thirty-three patients treated at 80 mg formed the efficacy set, and 39 formed the safety set. Most were heavily pretreated, and 69% had 2 or more metastatic sites. Baseline fecal samples from 32 patients were sequenced, split into 11 responders and 21 non-responders.
What were the most important findings?
The objective response rate was 15.2% and the disease control rate was 36.4%. Median progression-free survival was 2.1 months and median overall survival was 15.5 months. Response was higher without liver metastases than with them (30% versus 8.7%). All 3 patients with lung-only disease responded, whereas none of 4 with liver-only disease did. Non-responders had increased Fusobacteria and decreased Bacteroidetes at baseline. Patients with high abundance of a Fusobacteria-phylum genus had shorter progression-free survival than low-abundance patients (2.0 versus 5.2 months; p=0.002).
What are the greatest implications of this study?
The combination showed manageable safety and preliminary activity in a group historically unresponsive to PD-1 blockade alone. Patients without liver metastasis appeared to benefit most. A baseline gut genus in the Fusobacteria phylum emerged as a candidate predictive marker, hinting that lowering its abundance might improve outcomes. The sample was small, single-arm, and selected for good performance status, so the biomarker and efficacy signals need larger controlled trials before use.