Molecular mechanisms targeting drug-resistance and metastasis in colorectal cancer: Updates and beyond

Table 6 Combination of targeted therapies under clinical investigation for the treatment of drug-resistant and metastatic colorectal cancer

Agents	Targeted molecule (s)	Condition	Study phase	Clinical trial identifier
Encorafenib + Binimetinib + Cetuximab	Wild type plus BRAF V600E and MEK, EGFR	Previously untreated BRAF-mutant mCRC	Phase II	NCT03693170
Tucatinib + Trastuzumab	HER2	First-line HER2-positive mCRC	Phase III	NCT05253651
Disitamab + Vedotin + Tislelizumab	HER2 and PD-1	HER2-positive advanced CRC	Phase II	NCT05493683
Vanucizumab + Bevacizumab	VEGF-A/angiopoietin-2 and VEGF	mCRC	Phase II	NCT02141295
Regorafenib + Nivolumab	VEGFR1/2/3 and PD-1	Later-lines treatment of mCRC	Phase III	NCT05328908
Lenvatinib + Pembrolizumab	VEGFR1/2/3 and PD-1	mCRC	Phase III	NCT04776148
Fruquitinib + Camrelizumab	VEGFR tyrosine kinase and PD-1	Non-MSI-H/dMMR mCRC	Phase II	NCT04866862
Disitamab + Vedotin + Pembrolizumab	HER2 and PD-1	HER2-expressing mCRC	Phase II	NCT05333809
Cobimetinib + Atezolizumab	MAPK and PD-L1	mCRC	Phase III	NCT02788279
Cetuximab + Vemurafenib	EGFR and mutated BRAF V600E	BRAF V600E Mutated Advanced CRC	Phase II	NCT03727763
Penpulimab + Anlotinib	PD-1 and VEGFR1/2/3	Refractory mCRC	Phase II	NCT04970914
Favezelimab	LAG-3 and PD-1	Previously treated metastatic PD-L1 positive CRC	Phase III	NCT05064059
MEN1611 + Cetuximab	PI3K and EGFR	mCRC	Phase I/II	NCT04495621
Encorafenib + Cetuximab + Pembrolizumab	BRAF V600E, as well as wild-type BRAF, EGFR, andPD-1	Previously untreated mCRC	Phase II	NCT05217446
RXC004 + Nivolumab	Porcupine (wnt activator) and PD1	RNF43 or RSPO aberrated, metastatic, MSS CRC after progression on SOC	Phase II	NCT04907539
Regorafenib + Pembrolizumab	VEGFR1/2/3PD1	Advanced or mCRC	Phase I/II	NCT03657641
Isatuximab + Atezolizumab	Epitope on CD38, and PD-L1	mCRC	Phase I/II	NCT03555149
Atezolizumab + Selicrelumab + Bevacizumab	PD-L1, CD40 antigen, and VEGF	mCRC	Phase I/II	NCT03555149
Atezolizumab + Idasanutlin	PD-L1 and MDM2	mCRC	Phase I/II	NCT03555149
Atezolizumab + Regorafenib	PD-L1 andVEGFR1/2/3	mCRC	Phase I/II	NCT03555149
Olaparib (MK-7339) + Bevacizumab	PARP and VEGF	Unresectable or mCRC	Phase III	NCT04456699
Nivolumab + Ipilimumab	PD-1 andCTLA-4	dMMR and/or MSI mCRC resistant to anti-PD1 monotherapy	Phase II	NCT05310643
Nivolumab + Ipilimumab	PD-1 and CTLA-4	dMMR and/or MSI mCRC	Phase II	NCT04730544
Surufatinib + Sintilimab	VEGFR1/2/3 and PD-1	Advanced MSS-Type CRC	Phase II	NCT04764006
Camrelizumab + Apatinib	PD-1 and VEGFR-2	Advanced CRC	Phase I/II	NCT04067986
Fruquintinib + Tislelizumab + Stereotactic ablative radiotherapy	VEGFR1/2/3 and PD-1	mCRC	Phase II	NCT04948034
Avelumab + Cetuximab + mFOLFOXIRI	PD-1/PD-L1 and EGFR	Unresectable mCRC	Phase II	NCT04513951
Geptanolimab (GB226) + Fruquintinib	PD-1 and VEGFR1/2/3	mCRC	Phase I	NCT03977090
Selinexor + Pembrolizumab	Exportin 1 and PD-1	Previously treated mCRC with RAS mutations	Phase II	NCT04854434
Panitumumab + Rilotumumab	EGFR and HGF	wild-type KRAS mCRC	Phase I/II	NCT00788957
Panitumumab + Ganitumab	EGFR and IGF-1R	wild-type KRAS mCRC	Phase I/II	NCT00788957

MEK: Mitogen-activated extracellular signal-regulated kinase; EGFR: Epidermal growth factor receptor; mCRC: Metastatic colorectal cancer; HER2: Human epidermal growth factor receptor 2; PD-1: Programmed death-1; PD-L1: Programmed death ligand-1; VEGF-A: Vascular endothelial growth factor-A; VEGFR: Vascular endothelial growth factor receptor; MSI-H/dMMR: Microsatellite instability-high/mismatch repair deficient; MSS: Microsatellite stable; MAPK: mitogen-activated protein kinases; LAG-3 Lymphocyte activation gene 3; PI3K: Phosphoinositide 3-kinases; RNF43: Ring Finger Protein 43; RSPO: R-spondin; SOC: Standard of Care; PARP: Poly ADP ribose polymerase; CTLA-4: Cytotoxic T lymphocyte-associated antigen 4; HGF: Hepatocyte growth factor; IGF-1R: Insulin growth factor receptor-1.