Resistance to targeted therapy in metastatic colorectal cancer: Current status and new developments

Table 1 Strategies to reverse targeted therapy resistance in clinical trials

Target(s)	Agent(s)	Phase	Condition	Treatment	Main outcomes
EGFR ECD	Sym004	Phase I	KRAS-WT mCRC	Sym004	mOS: 12.8 mo
EGFR S468R	Necitumumab	Phase II	First-line mCRC	Necitumumab + mFOLFOX6	ORR: 63.6%
KRASG12C	Sotorasib (AMG 510)	Phase I	Solid tumors	Sotorasib	ORR: 7.1%; DCR: 73.8%
KRASG12C	Adagrasib (MRTX849)	Phase II	Solid tumors	Adagrasib	ORR: 17%; DCR: 94%
BRAF	Vemurafenib	Pilot trial	Previously treated	Vemurafenib + panitumumab	DCR: 83%
BRAF	Vemurafenib	Phase I	Previously treated	Irinotecan + vemurafenib	ORR: 35%; DCR: 88%; mPFS: 7.7m
BRAF	Vemurafenib	SWOG-S1406; phase II	Previously treated	Irinotecan + cetuximab + vemurafenib	mPFS: 4.2 mo; ORR: 17%; DCR: 65%
BRAF	Encorafenib	BEACON; phase III	Previously treated	Encorafenib + binimetinib + cetuximab	mOS: 9.3; ORR: 26.8%
BRAF	Dabrafenib	Phase I/II	BRAF-WT	Dabrafenib + trametinib	ORR: 12%
HER2	Dual-targeted drugs	HERACLE A; phase II	KRAS-WT	Trastuzumab + lapatinib	mOS: 11.5 mo; mPFS: 5.0 mo; ORR: 30%
HER2	Pertuzumab; T-DM1	HERACLE B; phase II	KRAS/BRAF-WT	Pertuzumab + trastuzumab	ORR: 9.7%; mPFS: 4.1 mo
HER2	Trastuzumab pertuzumab	MyPathway; phase II	Previously treated	Trastuzumab + pertuzumab	ORR: 32%; mOS: 11.5 mo; mPFS: 2.9 mo
HER2	Trastuzumab pertuzumab	TRIUMPH;phase II	KRAS-WT	Trastuzumab + pertuzumab	ORR: 30%; mOS: 10.1 mo; mPFS: 4.0 mo
HER2	ADC	DESTINY-CRC01; phase II	Previously treated	Trastuzumab deruxtecan (T-DXd)	ORR: 45.3%; mOS: 15.5 mo; mPFS: 6.9 mo
HER2	Tucatinib	MOUNTAINEER; phase II	Previously treated	Tucatinib + trastuzumab	ORR: 52%; mOS: 18.7 mo; mPFS: 8.1 mo
MET	Tivantinib	Phase II	KRAS WT; previously treated	Tivantinib + irinotecan + cetuximab	mPFS: 8.3 mo; ORR: 44%; mOS: 19.8 mo
EGFR rechallenge	Irinotecan	CRICKET; phase II	KRAS/BRAF WT; third-line	Irinotecan + cetuximab	ORR: 21%; DCR: 54%; mOS: 9.8 mo; mPFS: 3.4 mo
EGFR rechallenge	Avelumab	CAVE; phase II	KRAS WT; third-line	Avelumab + cetuximab	mOS: 11.6 mo; mPFS: 3.6 mo; ORR: 7.8%; DCR: 65%
EGFR rechallenge	Irinotecan	REMARRY and PURSUIT; phase II	KRAS/BRAF WT	Panitumumab + irinotecan	ORR: 14%; mPFS: 3.6 mo
VEGF	Vanucizumab	Phase I	Solid tumors	Vanucizumab	DCR: 59.8%; mPFS: 2.8 mo
VEGF	Bevacizumab	TRIBE; phase II	mCRC	Bevacizumab + FOLFOXIRI	mPFS: 12.1 mo; mOS: 30.9 mo
VEGF	Aflibercept	VALOUR; phase III	Previously treated	Aflibercept + FOLFIRI	mOS: 13.5 mo; mPFS: 6.9 mo
VEGF	Aflibercept	AFFIRM; phase II	First-line	Aflibercept + FOLFOX	mPFS: 8.48 mo; 12mPFS: 25.8%
VEGF	Ramucirumab	RAISE; phase III	Second-line	Ramucirumab + FOLFIRI	mOS: 13.3 mo
VEGF	Bevacizumab	C-TASK FORCE; phase I/II	Previously treated	Bevacizumab + trifluridine/tipiracil	16 wk PFS: 46.9%
TKI	Famitinib	Phase II	Previously treated	Famitinib	mPFS: 2.8 mo; mOS: 7.4 mo; DCR: 59.8%; ORR: 2.2%
NTRK	Larotrectinib	NAVIGATE; phase I/II	Solid tumors	Larotrectinib	ORR: 50%; DCR: 100%; mPFS: 5.5 mo; mOS: 29.4 mo
PD-1/PD-L1	Pembrolizumab	KEYNOTE-177; phase III	dMMR/MSI-H CRC; first-line	Pembrolizumab	mPFS: 16.5 mo; mOS: NA
PD-1/PD-L1	Nivolumab	CheckMate-142; phase II	dMMR/MSI-H CRC; previously treated	Nivolumab	ORR: 60%; DCR: 84%
PD-1/PD-L1	Durvalumab	Phase I	Solid tumors	Durvalumab + tremelimumab	DCR: 36.4%
PD-1/PD-L1	Durvalumab	Phase Ib/II	MSS RAS/BRAF WT	Durvalumab + tremelimumab + FOLFOX	ORR: 81%; DCR: 89%
PD-1/PD-L1	Nivolumab	Phase Ib	MSS	Nivolumab + regorafenib	mPFS: 7.9 mo
PD-1/PD-L1	Durvalumab	Phase II	Chemotherapy-refractory MSS	Durvalumab + tremelimumab + radiotherapy	ORR: 8.3%; mPFS: 1.8 mo; mOS: 11.4 mo

mCRC: Metastatic colorectal cancer; EGFR: Epidermal growth factor receptor; VEGF: Vascular endothelial growth factor; TKI: Tyrosine kinase inhibitors; ADC: Antibody-drug conjugate; ORR: Overall response rate; mOS: Median overall survival; mPFS: Median progression-free survival; DCR: Disease control rate; PD-1: Programmed cell death protein 1; PD-L1: Programmed death-ligand 1; MSS: Microsatellite stable; FOLFOX: Leucovorin, 5-fluorouracil, and oxaliplatin; FOLFIRI: Leucovorin, 5-fluorouracil, and irinotecan; T-DXd: Trastuzumab deruxtecan; HER: Human epidermal growth factor receptor.