Regorafenib plus toripalimab in patients with metastatic colorectal cancer: a phase Ib/II clinical trial and gut microbiome analysis

Study information

Reviewed Marked as Reviewed by Peace Sandy on 2024-1-25

study design

randomized controlled trial

Citation

PMID PubMed identifier for scientific articles.

34622226

DOI Digital object identifier for electronic documents.

https://doi.org/10.1016/j.xcrm.2021.100383

URI

https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(21)00237-8

Authors

Wang F, He MM, Yao YC, Zhao X, Wang ZQ, Jin Y, Luo HY, Li JB, Wang FH, Qiu MZ, Lv ZD, Wang DS, Li YH, Zhang DS, Xu RH

Journal

Cell reports. Medicine

Year

2021

Keywords:

colorectal cancer, immunotherapy, microbiome, programmed cell death protein 1, regorafenib, toripalimab

This is a phase Ib/II study of regorafenib plus toripalimab for colorectal cancer. The objective response rate (ORR) is 15.2% and the disease control rate is 36.4% in evaluable patients with recommended phase II dose (80 mg regorafenib plus toripalimab). The median progression-free survival (PFS) and the median overall survival are 2.1 months and 15.5 months, respectively. Patients with liver metastases have lower ORR than those without (8.7% versus 30.0%). All patients (3/3) with lung-only metastasis respond, whereas no patients (0/4) with liver-only metastasis respond. 94.9% and 38.5% of patients have grade 1 and grade 3 treatment-related adverse events, respectively. Gut microbiome analysis of the baseline fecal samples shows significantly increased relative abundance and positive detection rate of Fusobacterium in non-responders than responders. Patients with high-abundance Fusobacterium have shorter PFS than those with low abundance (median PFS = 2.0 versus 5.2 months; p = 0.002).

Experiment 1

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Reviewed Marked as Reviewed by Peace Sandy on 2024-1-25

Curated date: 2022/10/09

Curator: Mary Bearkland

Revision editor(s): LGeistlinger, Mary Bearkland, Peace Sandy, Davvve

Subjects

Location of subjects: China

Host species Species from which microbiome was sampled. Contact us to have more species added.: Homo sapiens

Body site Anatomical site where microbial samples were extracted from according to the Uber Anatomy Ontology: Feces Cow dung,Cow pat,Droppings,Dung,Excrement,Excreta,Faeces,Fecal material,Fecal matter,Fewmet,Frass,Guano,Matières fécales@fr,Merde@fr,Ordure,Partie de la merde@fr,Piece of shit,Porción de mierda@es,Portion of dung,Portion of excrement,Portion of faeces,Portion of fecal material,Portion of fecal matter,Portion of feces,Portion of guano,Portion of scat,Portionem cacas,Scat,Spoor,Spraint,Stool,Teil der fäkalien@de,Feces,feces

Condition The experimental condition / phenotype studied according to the Experimental Factor Ontology: Colorectal cancer cancer of colorectum,cancer of large bowel,cancer of large intestine,cancer of the large bowel,colon cancer,colorectal cancer,colorectum cancer,CRC,large intestine cancer,malignant colorectal neoplasm,malignant colorectal tumor,malignant colorectum neoplasm,malignant large bowel neoplasm,malignant large bowel tumor,malignant large intestine neoplasm,malignant large intestine tumor,malignant neoplasm of colorectum,malignant neoplasm of large bowel,malignant neoplasm of large intestine,malignant neoplasm of the large bowel,malignant neoplasm of the large intestine,malignant tumor of large bowel,malignant tumor of large intestine,malignant tumor of the large bowel,malignant tumor of the large intestine,Colorectal cancer

Group 0 name Corresponds to the control (unexposed) group for case-control studies: Non-responders (Progressive Disease)

Group 1 name Corresponds to the case (exposed) group for case-control studies: Responders (Partial Response or Stable Disease)

Group 1 definition Diagnostic criteria applied to define the specific condition / phenotype represented in the case (exposed) group: Patients with histologically confirmed metastatic or unresectable MSS/MSI-L/pMMR colorectal cancer treated with 80 mg, or 120 mg regorafenib, plus toripalimab resulting in stable disease or partial response.

Group 0 sample size Number of subjects in the control (unexposed) group: 21

Group 1 sample size Number of subjects in the case (exposed) group: 11

Antibiotics exclusion Number of days without antibiotics usage (if applicable) and other antibiotics-related criteria used to exclude participants (if any): Any condition requiring ongoing systemic antibiotic therapy

Lab analysis

Sequencing type: 16S

16S variable region One or more hypervariable region(s) of the bacterial 16S gene: V3-V4

Sequencing platform Manufacturer and experimental platform used for quantifying microbial abundance: Illumina

Statistical Analysis

Data transformation Data transformation applied to microbial abundance measurements prior to differential abundance testing (if any).: relative abundances

Statistical test: LEfSe

Significance threshold p-value or FDR threshold used for differential abundance testing (if any): 0.05

LDA Score above Threshold for the linear discriminant analysis (LDA) score for studies using the popular LEfSe tool: 3

Alpha Diversity

Shannon Estimator of species richness and species evenness: more weight on species richness: decreased

Signature 1

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Reviewed Marked as Reviewed by Peace Sandy on 2024-1-25

Curated date: 2022/10/09

Curator: Mary Bearkland

Revision editor(s): Mary Bearkland, Aiyshaaaa, Peace Sandy

Source: Supp table S3

Description: Linear discriminant analysis effect size (LDA) from phylum to species level shows differentially enriched taxa in NR and R groups. Related to Figure 4. R, response; NR, non-response.

Abundance in Group 1: increased abundance in Responders (Partial Response or Stable Disease)

NCBI	Quality Control	Links
Dialister massiliensis
Selenomonadales
Veillonellales
Paraprevotella

Revision editor(s): Mary Bearkland, Aiyshaaaa, Peace Sandy

Signature 2

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Reviewed Marked as Reviewed by Peace Sandy on 2024-1-25

Curated date: 2022/10/09

Curator: Mary Bearkland

Revision editor(s): Mary Bearkland, Aiyshaaaa, Peace Sandy

Source: Supp table S3

Description: Linear discriminant analysis effect size (LDA) from phylum to species level shows differentially enriched taxa in NR and R groups. Related to Figure 4. R, response; NR, non-response.

Abundance in Group 1: decreased abundance in Responders (Partial Response or Stable Disease)

NCBI	Quality Control	Links
Acidaminococcaceae
Acidaminococcales
Acidaminococcus
Alistipes
Bilophila
Desulfovibrionaceae
Desulfovibrionales
Desulfovibrionia
Fusobacteriaceae
Fusobacteriales
Fusobacteriia
Fusobacteriota
Fusobacterium
Fusobacterium sp.
Lachnoclostridium
Marinifilaceae
Oscillospiraceae
Rikenellaceae
Thermodesulfobacteriota
unclassified Acidaminococcus
unclassified Alistipes
uncultured Bilophila sp.

Revision editor(s): Mary Bearkland, Aiyshaaaa, Peace Sandy