Microbiota-driven immunometabolic regulation in colorectal cancer: Mechanisms and therapeutic opportunities

Table 1 The immune checkpoint, metabolic inhibitors and gut microbiota currently under clinical investigation for the treatment of colorectal cancer

	Drug	Targets	Clinical phase	NCT	Sponsored by	Status	Purpose
ICIs	Relatlimab	LAG-3	Phase 2	NCT03642067	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins	Completed	The purpose of this study is to evaluate the safety and clinical activity of nivolumab and relatlimab in patients with metastatic or locally advanced MSS colorectal cancer
	MK-4830	ILT-4	Phase 2	NCT04895722	Merck Sharp & Dohme LLC	Active, not recruiting	Evaluation of co-formulated pembrolizumab/quavonlimab (MK-1308A) vs other treatments in participants with MSI-H or dMMR stage IV CRC (MK-1308A-008/KEYSTEP-008)
	Tucatinib	HER2	Phase 3	NCT05253651	Seagen, a wholly owned subsidiary of Pfizer	Recruiting	A study of tucatinib with trastuzumab and mFOLFOX6 vs standard of care treatment in first-line HER2+ metastatic CRC (MOUNTAINEER-03)
	B1962	VEGF/PD-L1	Phase 2	NCT04296019	Tasly Biopharmaceuticals Co., Ltd.	Not yet recruiting	A multicenter, open phase IIb clinical study to evaluate the efficacy and safety of B1962 injection in the treatment of advanced CRC
	MGD007	GPA33	Phase 1	NCT02248805	MacroGenics	Completed	Phase 1 study of MGD007 in relapsed/refractory metastatic colorectal carcinoma
	Belzutifan	HIF-2α	Phase 2	NCT04976634	Merck Sharp & Dohme LLC	Active, not recruiting	Pembrolizumab plus lenvatinib in combination with belzutifan in solid tumors (MK-6482-016)
	PF-07062119	GUCY2c/CD3	Phase 1	NCT04171141	Pfizer	Terminated	Study to test the safety and tolerability of PF-07062119 in patients with selected advanced or metastatic gastrointestinal tumors
	BMS-986340	CCR8	Phase 1 and phase 2	NCT04895709	Bristol-Myers Squibb	Recruiting	A study of BMS-986340 as monotherapy and in combination with nivolumab or docetaxel in participants with advanced solid tumors
	Sintilimab	PD-1	Phase 3	NCT05236972	Sun Yat-sen University	Recruiting	PACE: PD-1 antibody for dMMR/MSI-H stage III CRC
	Avelumab	PD-L1	Phase 2	NCT03854799	Gruppo Oncologico del Nord-Ovest	Completed	Immunotherapy in locally advanced rectal cancer (AVANA)
	Tislelizumab	PD-1	Phase 1 and phase 2	NCT04577963	Hutchison Medipharma Limited	Terminated	A study of fruquintinib in combination with tislelizumab in advanced solid tumors
	Pembrolizumab	PD-1	Phase 2	NCT05131919	The Netherlands Cancer Institute	Active, not recruiting	Pembrolizumab for locally advanced, irresectable, non-metastatic dMMR CRCs (PUMA)
	Nivolumab	PD-1	Phase 2	NCT03642067	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins	Completed	The purpose of this study is to evaluate the safety and clinical activity of nivolumab and relatlimab in patients with metastatic or locally advanced MSS CRC
	HFB200603	BTLA	Phase 1	NCT05789069	HiFiBiO Therapeutics	Recruiting	A study of HFB200603 as a single agent and in combination with tislelizumab in adult patients with advanced solid tumors
	MK0457	pan-Aurora	Phase 1	NCT00099346	Merck Sharp & Dohme LLC	Terminated	MK0457 (an aurora kinase inhibitor) study in patients with advanced CRC and other advanced solid tumors (0457-001)
	HRO761	WRN	Phase 1	NCT05838768	Novartis Pharmaceuticals	Recruiting	Study of HRO761 alone or in combination in cancer patients with specific DNA alterations called microsatellite instability or mismatch repair deficiency
Metabolic inhibitor	Epacadostat	IDO1	Phase 1 and phase 2	NCT03516708	Washington University School of Medicine	Recruiting	Epacadostat (INCB024360) added to preoperative chemoradiation in patients with locally advanced rectal cancer
	Ivosidenib	IDH1	Phase 2	NCT04195555	National Cancer Institute	Active, not recruiting	Ivosidenib in treating patients with advanced solid tumors, lymphoma, or histiocytic disorders with IDH1 mutations (a pediatric MATCH treatment trial)
	Metformin	Mitochondria	Phase 3	NCT05921942	Ain Shams University	Completed	The impact of metformin administration on the clinical outcome of stage IV colon cancer
	Telaglenastat	GLS	Phase 1 and phase 2	NCT02861300	David Bajor, MD	Completed	CB-839 + capecitabine in solid tumors and fluoropyrimidine resistant PIK3CA mutant CRC
Gut microbiota	Gut microbiota	/	Observational	NCT02845973	Shanghai Jiao Tong University School of Medicine	Completed	Study of fecal bacteria in early diagnosis of CRC
	Gut microbiota	/	Observational	NCT06738173	Gianluca Ianiro, Catholic University of the Sacred Heart (Responsible Party)	Recruiting	Microbiome-based diagnostic tool for the screening of CRC (GUILTI)
	Gut microbiota	/	Observational	NCT06588166	Fondazione Policlinico Universitario Agostino Gemelli Irccs	Recruiting	Microbiome testing for the screening of CRC (NI-GUILTI)
	Gut microbiota	/	Observational	NCT04291755	Persephone Biosciences (Responsible Party)	Recruiting	Development and analysis of a stool bank for cancer patients
	Gut microbiota		Observational (patient registry)	NCT07154173	Sixth Affiliated Hospital, Sun Yat-sen University	Recruiting	Comprehensive analysis of gut microbiota signatures in metastatic CRC
	Fusobacterium nucleatum		Interventional	NCT05945082	Malmö University	Recruiting	Fusobacterium nucleatum at CRC sites
	EPEC		Observational (patient registry)	NCT02373020	Mansoura University	Recruiting	EPEC: Does it have a role in colorectal tumourigenesis (EPEC)?

MSS: Microsatellite stable; MSI-H: High microsatellite instability; dMMR: Mismatch repair deficient; CRC: Colorectal cancer; EPEC: Enteropathogenic Escherichia coli; ICI: Immune checkpoint inhibitor; NCT: National clinical trial; VEGF: Vascular endothelial growth factor; PD-L1: Programmed death ligand-1; PACE: Pembrolizumab adjuvant colorectal evaluation; PD-1: Programmed death 1; PUMA: Pembrolizumab for unresectable high microsatellite instability/mismatch repair deficient advanced colorectal cancer; GUILTI: Gut microbiota-based diagnostic tool for the screening of colorectal cancer; NI-GUILTI: Non-invasive gut microbiota-based diagnostic tool for the screening of colorectal cancer.