Impact of liver metastasis on the efficacy of immune checkpoint inhibitors for advanced colorectal cancer

Table 1 Characteristics of the included studies

Ref.	Country	Design	Diagnosis	Number of patients	Mean age (years)	Men (%)	Number of patients with LM	ICIs used	Concurrent treatment	Median follow-up duration (months)	Outcomes reported	Variables adjusted
Schrock et al[15], 2019	United States	RC	MSI-H mCRC	22	52	45.5	10	Pembrolizumab, nivolumab/ipilimumab, or durvalumab/tremelimumab	NR	18	PFS and OS	Age, sex, tumor stage, grade, location, and TMB
Loupakis et al[16], 2020	Italy	PC	MSI-H mCRC	80	60	56.2	25	Nivolumab, pembrolizumab, or nivolumab/ipilimumab	NR	22.8	PFS and OS	None
Yang et al[19], 2022	China	RC	mCRC without confirmed MSI-H/dMMR status	84	63	60	55	Sintilimab, nivolumab, toripalimab, camrelizumab, pembrolizumab, and tislelizumab	Regorafenib	5.5	PFS	Age, ECOG-PS, RAS mutation status and site of primary tumor
Sun et al[18], 2021	China	RC	MSS mCRC	51	54.2	52.9	38	Toripalimab, nivolumab, sintilimab, or camrelizumab	Fruquintinib or regorafenib	6.2	PFS	Age, sex, ECOG-PS at baseline, first diagnosis time, tumor location, RAS mutation status, and previous therapy
Sahin et al[17], 2021	United States	RC	dMMR MSI-H mCRC	60	NR (> 50)	55	11	Pembrolizumab, nivolumab, or nivolumab/ipilimumab	NR	28.3	PFS	Age, MMR genes, and BRAF V600E mutation
Li et al[20], 2022	China	RC	pMMR/MSS mCRC	103	56	54.4	59	Nivolumab, pembrolizumab, camrelizumab, sintilimab, or toripalimab	Regorafenib	5.3	OS	None
Nie et al[21], 2022	China	PC	MSS mCRC	72	57	50	44	Sintilimab	Fruquintinib or regorafenib	13	PFS and OS	None
Zhang et al[22], 2022	China	RC	MSS mCRC	110	53	57.3	60	Sintilimab, camrelizumab, toripalimab, tislelizumab, and pembrolizumab	Fruquintinib	22.4	PFS	Age, sex, baseline ECOG-PS, site of primary tumor, lines of treatment, RAS and BRAF mutation status, previous treatment, ALP, and TMB
Chen et al[23], 2023	Canada	Post-hoc analysis of RCT	mCRC unselected for MSI status	119	65	67.2	80	Durvalumab plus tremelimumab	NR	15	PFS and OS	Age, sex, and TMB
Saberzadeh-Ardestani et al[24], 2023	United States	RC	dMMR mCRC	41	81	29	14	Pembrolizumab	None	23	PFS	Age, sex, primary tumor location, histological grade, PS at baseline, the number of sites of metastatic disease and CEA
Yang et al[25], 2023	China	RC	MSS/pMMR mCRC	70	59	52.9	51	Nivolumab, pembrolizumab, tislelizumab, sintilimab, and toripalimab	Fruquintinib	17.2	PFS and OS	Age, sex, metastatic site, KRAS mutant, low BMI, primary lesion resected, and lines of ICIs treatment
Zhao et al[28], 2024	China	RC	MSS/pMMR mCRC	143	59	68.5	93	Pembrolizumab, nivolumab, sintilimab, tislelizumab, camrelizumab, and durvalumab	TKI, bevacizumab or cetuximab, or chemotherapy	23.1	PFS and OS	Age, sex, ECOG-PS, primary tumor site, number of metastases, RAS and BRAF mutation status, previous treatment, and lines of ICIs treatment
Kim et al[26], 2024	United States	PC	MSS/pMMR mCRC	51	56	53.8	37	Nivolumab	Regorafenib	15	PFS and OS	Age, sex, race, obesity, albumin, ECOG-PS, primary tumor side, RAS mutation status, and previous treatment
Saberzadeh-Ardestani et al[27], 2024	France	RC	dMMR mCRC	66	64	45	17	Pembrolizumab, nivolumab, or avelumab	NR	24.3	PFS	Age, sex, PS, primary tumor site, and number of metastatic sites
Fakih et al[29], 2024	United States	RC	MSS mCRC	96	58	55.2	33	Nivolumab alone, or ipilimumab and nivolumab	Regorafenib	18	PFS and OS	None
Fakih et al[30], 2024	United States	RC	MSI-H mCRC	35	56	51.4	12	Pembrolizumab, nivolumab and ipilimumab, or durvalumab in combination with tremelimumab	NR	42	PFS and OS	None

NR: Not reported; RC: Retrospective cohort; PC: Prospective cohort; RCT: Randomized controlled trial; mCRC: Metastatic colorectal cancer; MSI-H: Microsatellite instability-high; MSS: Microsatellite stable; dMMR: Mismatch repair-deficient; pMMR: Mismatch repair-proficient; ICIs: Immune checkpoint inhibitors; PFS: Progression-free survival; OS: Overall survival; ECOG-PS: Eastern Cooperative Oncology Group performance status; TMB: Tumor mutational burden; ALP: Alkaline phosphatase; CEA: Carcinoembryonic antigen; TKI: Tyrosine kinase inhibitor; BMI: Body mass index; PS: Performance status.

Table 2 Study quality evaluation via the Newcastle-Ottawa Scale

Ref.	Representativeness of the exposed cohort	Selection of the non-exposed cohort	Ascertainment of exposure	Outcome not present at baseline	Control for age	Control for other confounding factors	Assessment of outcome	Enough long follow-up duration	Adequacy of follow-up of cohorts	Total
Schrock et al[15], 2019	0	1	1	1	1	1	1	1	1	8
Loupakis et al[16], 2020	1	1	1	1	0	0	1	1	1	7
Yang et al[19], 2022	0	1	1	1	1	1	1	0	1	7
Sun et al[18], 2021	0	1	1	1	1	1	1	0	1	7
Sahin et al[17], 2021	0	1	1	1	1	1	1	1	1	8
Li et al[20], 2022	0	1	1	1	0	0	1	1	1	6
Nie et al[21], 2022	1	1	1	1	0	0	1	1	1	7
Zhang et al[22], 2022	1	1	1	1	1	1	1	1	1	9
Chen et al[23], 2023	0	1	1	1	1	1	1	1	1	8
Saberzadeh-Ardestani et al[24], 2023	1	1	1	1	1	1	1	1	1	9
Yang et al[25], 2023	0	1	1	1	1	1	1	1	1	8
Zhao et al[28], 2024	0	1	1	1	1	1	1	1	1	8
Kim et al[26], 2024	0	1	1	1	1	1	1	1	1	8
Saberzadeh-Ardestani et al[27], 2024	0	1	1	1	1	1	1	1	1	8
Fakih et al[29], 2024	0	1	1	1	0	0	1	1	1	6
Fakih et al[30], 2024	0	1	1	1	0	0	1	1	1	6