Table 2.

Chemotherapy and targeted therapies for metastatic colorectal cancer patients

Ref.	Country	Drug(s)	Number of patients	Study phase	ORR, %	Mean OS in mo	Mean PFS in mo	Results
Resectable CLM with no extra-hepatic metastasis
Gruenberger et al[42]	Austria	Capecitabine, oxaliplatin plus bevacizumab	56	2	73.2	-	-	Bevacizumab can be safely administered until 5 wk before liver resection in patients with metastatic CRC without increasing the rate of surgical or wound healing complications or the severity of bleeding
Bridgewater et al[43]	United Kingdom	Oxaliplatin, L-folinic acid, fluorouracil or capecitabine, oxaliplatin plus cetuximab	257	3	-	81.0/55.4 (Chemo/Chemo+)	22.2/15.5 (Chemo/Chemo+)	In the perioperative setting, patients with operable diseases are at a disadvantage in terms of OS; hence, cetuximab should not be used in this setting
Unresectable CLM with potential for resection and no extra-hepatic metastasis
Wong et al[44]	United Kingdom	Capecitabine, oxaliplatin plus bevacizumab	46	-	78.0	-	-	A high response rate for patients with CLMs with poor-risk features not selected for upfront resection and converted 40% of patients to resectability
Gruenberger et al[45]	United Kingdom, Austria, France, and Spain	Bevacizumab plus FOLFOX-6 (5-fluorouracil folinic acid oxaliplatin) or FOLFOXIRI (5-fluorouracil folinic acid oxaliplatin irinotecan)	80	2	81/62 (BF/BF6)	-	18.6/11.5 (BF/BF6)	In patients with CLM that were originally unresectable, bevacizumab-FOLFOXIRI was correlated with better response and resection rates as well as a longer PFS than bevacizumab-mFOLFOX-6
Garufi et al[47]	Italy	Cetuximab plus chrono-IFLO (chrono-irinotecan 5-fluorouracil leucovorin oxaliplatin)	43	2	-	37	-	Cetuximab in combination with chrono-IFLO resulted in 60% full resectability of CLM patients
Folprecht et al[48]	Germany	Cetuximab plus FOLFOX (5-fluorouracil folinic acid oxaliplatin) or FOLFOXIRI (5-fluorouracil folinic acid oxaliplatin irinotecan)	56/55 (CFX/CFI)	-	-	35.7/29.0 (CFX/CFI)	10.8/10.5 (CFX/CFI)	Both FOLFOX/FOLFIRI with cetuximab appear to be effective conversion therapy regimens in patients with KRAS codon 12/13/61 wild-type tumors. Thus, liver surgery can be deemed curative or as a second line of therapy in people who are not cured
Unresectable CLM
Rivera et al[50]	Spain, Germany, United States, Belgium, Switzerland, and Italy	mFOLFOX6 plus panitumumab or bevacizumab	170/156 (RAS WT/RAS WT/BRAF WT)	-	RAS WT 65/60, RAS WT/BRAF WT 65/62 (FXP/FXB)	RAS WT 36.9/28.9, RAS WT/BRAF WT 46.3/28.9 (FXP/FXB)	RAS WT 12.8/10.1, RAS WT/BRAF WT 13.1/10.1 (FXP/FXB)	Panitumumab in combination with mFOLFOX6 is a successful first-line therapy for individuals with RAS WT and RAS WT/BRAF WT mCRC
Stintzing et al[53]	Germany	FOLFIRI (5-fluorouracil leucovorin irinotecan) plus cetuximab or bevacizumab	400	3	65.3/58.7 (FIC/FIB)	33.1/25.0 (FIC/FIB)	10.3/10.2 (FIC/FIB)	In the first-line therapy of patients with RAS wild-type metastatic colorectal cancer, FOLFIRI with cetuximab may be preferable than FOLFIRI plus bevacizumab
Pfeiffer et al[58]	Denmark	Trifluridine plus tipiracil hydrochloride (TAS-102) or TAS-102 plus bevacizumab	47/46 (T/TB)	2	51/67 (T/TB)	6.7/9.4 (T/TB)	2.6/4.6 (T/TB)	In terms of efficacy and safety, bevacizumab may be an effective companion for TAS-102 in patients with chemorefractory metastatic colorectal cancer
Cremolini et al[59]	Italy	Cetuximab plus irinotecan	13/12 (RWT/RMT)	2	-	12.5/5.2 (RWT/RMT)	4.0/1.9 (RWT/RMT)	In patients with RAS and BRAF wild-type mCRC who have acquired resistance to first-line irinotecan and cetuximab-based treatment, a re-challenge approach with cetuximab and irinotecan may be effective. The examination of RAS mutational status on cDNA may aid in the selection of potential patients
Sartore-Bianchi et al[60]	Italy	Panitumumab (re-challenge)	25	-	30	13.7	4	Interventional liquid biopsies can be used efficiently and safely to guide anti-EGFR re-challenge treatment with panitumumab in patients with mCRC
Kopetz et al[63]	United States	Irinotecan cetuximab or irinotecan cetuximab plus vemurafenib	50/50 (IC/ICV)	-	-	12/12 (IC/ICV)	2.0/4.2 (IC/ICV)	Vemurafenib in combination with cetuximab and irinotecan is an active combination that increases PFS. This is a well-planned research based on a solid grasp of the mechanisms of adaptive resistance in mCRC
Tabernero et al[64]	United States, France, Italy, Spain, United Kingdom, Germany, Australia, Hong Kong, Norway, Switzerland, Japan, South Korea, and the Netherlands	Encorafenib cetuximab binimetinib or encorafenib cetuximab or FOLFIRI cetuximab	224/220/221 (3D/2D/CD)	3	26.8/19.5/1.8 (3D/2D/CD)	9.3/9.3/5.9 (3D/2D/CD)	-	When compared to conventional chemotherapy, encorafenib plus cetuximab improved OS, ORR, and progression-free survival in previously treated patients with metastatic disease. Encorafenib with cetuximab is a new standard-of-care regimen for previously treated patients with BRAF V600E mCRC, according to main and revised studies
Siena et al[68]	United States, Italy, United Kingdom, Spain, and Japan	Trastuzumab deruxtecan (DS-8201)	53/7/18 (A/B/C)	2	45.3 (A)	5.4 (A)	6.9 (A)	Trastuzumab deruxtecan shown promising and sustained effect in HER2-positive mCRC that was resistant to conventional therapy, as well as a favorable safety profile
Mayer et al[71]	Belgium, Italy, Japan, Spain, Australia, and United States	Trifluridine plus tipiracil hydrochloride (TAS-102) or placebo	800 (2:1)	-	1.6/0.4 (TAS/placebo)	7.1/5.3 (TAS/placebo)	2.0/1.7 (TAS/placebo)	A significant number of Japanese and Western patients with mCRC who had had a lot of prior treatment, including those whose condition was resistant to fluorouracil, were shown to respond clinically to TAS-102

2D: Encorafenib plus cetuximab; 3D: Encorafenib plus cetuximab plus binimetinib; A: Cohort A; B: Cohort B; BF: Bevacizumab plus FOLFOXIRI; BF6: Bevacizumab plus FOLFOX-6; BRAF: Protein kinase B-Raf; C: Cohort C; CD: FOLFIRI plus cetuximab; CFI: Cetuximab plus FOLFOXIRI; CFX: Cetuximab plus FOLFOX; CRC: Colorectal cancer; EGFR: Epidermal growth factor receptor; FIB: FOLFIRI plus bevacizumab; FIC: FOLFIRI plus cetuximab; FOLFIRI: Folinic acid, fluorouracil, and irinotecan hydrochloride; FXB: mFOLFOX6 plus bevacizumab; FXP: mFOLFOX6 plus panitumumab; HER2: Human epidermal growth factor receptor 2; IC: Irinotecan plus cetuximab; ICV: Irinotecan plus cetuximab plus vemurafenib; mCRC: Metastatic colorectal cancer; ORR: Objective response rate; OS: Overall survival; PFS: Progression-free survival; RAS: Rat sarcoma virus; RMT: Rat sarcoma virus mutate-type; RWT: Rat sarcoma virus wild-type; T: Trifluridine plus tipiracil hydrochloride; TB: Trifluridine plus tipiracil hydrochloride plus bevacizumab; WT: Wild-type.