Table 3.

Trials prospectively assessing the role of liquid biopsy in mCRC

Study	Study population	Liquid biopsy analysis	Primary endpoints
Observational studies
COLOMATE (NCT03765736)	Locally advanced and/or mCRC	ctDNA	To facilitate accrual to molecularly assigned therapies; to facilitate clinically annotated genomic analyses
PERMED01 (NCT02342158)	Locally advanced and metastatic malignancies	ctDNA and CTCs	To facilitate accrual to molecularly assigned therapies
TARGET	Locally advanced and metastatic malignancies	ctDNA	To match patients with a broad range of advanced cancers to early-phase clinical trials based on ctDNA analysis
NCT03594448	MSI mCRC	ctDNA	To test concordance between MSI status in ctDNA and primary tumor tissues; to correlate MSI ctDNA changes with response to therapy
RASINTRO (NCT03259009)	mCRC under treatment with anti-EGFR MoAb rechallenge	ctDNA	To correlate ctDNA RAS MT with PFS of anti-EGFR rechallenge
OPTIMAL-II (NCT03750175)	mCRC under treatment with anti-EGFR MoAb	ctDNA	Feasibility and reliability of cfDNA-based selection of KRAS, NRAS, and BRAF WT Patients with mCRC who will benefit from anti-EGFR MoAb and cfDNA analysis during therapy and at time of progression
NCT03401957	mCRC treated with cetuximab-based infusional 5-fluorouracil regimen as first line	ctDNA	To observe the percentage and the time to onset of RAS MT
PERSEIDA (NCT02792478)	RAS WT mCRC in first-line treatment	ctDNA	To evaluate the appearance of new RAS MT at disease progression and prior to radiological documentation
PREDATOR (ESMO 2020, Loupakis et al)	Oligometastatic CRC treated with curative intent	ctDNA	To evaluate PFS according to post-operative ctDNA status
Interventional studies
Study and phase of research	Study population	Liquid biopsy analysis	Intervention	Primary endpoints
NCT03436563 Phase Ib/II	Resected mCRC with detectable ctDNA following resection of all known liver metastases (cohort D)	ctDNA	M7824 (anti-PD-L1/TGF-beta-RII fusion protein) for 6 doses after resection and completion of standard-of-care therapy	ctDNA clearance
CHRONOS (NCT03227926) Phase II	RAS/BRAF WT mCRC previously sensitive to anti-EGFR MoAb and then progressed, after ≥1 following line of therapy, with >50% drop in RAS mutational load at serial ctDNA analyses or absent RAS MT/EGFR ectodomain MT ctDNA	ctDNA	Rechallenge of third-line panitumumab monotherapy	ORR
NCT03087071 Phase II	RAS/BRAF WT mCRC with clinical benefit and then progression to anti-EGFR MoAb	ctDNA	Rechallenge of panitumumab monotherapy in patients with EGFR ectodomain MT ctDNA or without neither EGFR ectodomain nor KRAS/NRAS/BRAF MT ctDNA; panitumumab and trametinib in patients with KRAS/NRAS/BRAF MT ctDNA	ORR
CAPRI 2-GOIM	RAS/BRAF WT anti-EGFR refractory mCRC	ctDNA	Continuum of treatment with cetuximab if RAS WT ctDNA; second-line FOLFOX and bevacizumab if RAS MT ctDNA and then third-line rechallenge with cetuximab and irinotecan if back to RAS WT ctDNA or standard-of-care therapy if persistent RAS MT ctDNA	ORR
NCT03844620 Phase II	Pretreated mCRC	ctDNA	Comparison of either regorafenib or TAS-102 continuation based on early changes in ctDNA analysis or according to standard of care	Early change in ctDNA as a predictor of radiographic progression; comparison of adverse events between ctDNA and standard-of-care arms
MoLiMoR (NCT04554836) Phase II	RAS MT mCRC	ctDNA	Comparison of FOLFIRI vs FOLFIRI plus intermittent addition of cetuximab when ctDNA analysis demonstrates conversion to RAS WT	PFS
VISNÙ-1 (NCT01640405) Phase III	Previously untreated patients with mCRC with ≥3 CTCs/7.5 mL	CTCs	Comparison of first-line FOLFOX plus bevacizumab vs FOLFOXIRI plus bevacizumab	PFS
VISNÙ-2 (NCT01640444) Phase II	Previously untreated patients with KRAS WT mCRC with <3 CTCs/7.5 mL	CTCs	Comparison of first-line FOLFIRI plus bevacizumab vs FOLFIRI plus cetuximab based on BRAF and PI3K mutational status	PFS

CTCs circulating tumor cells, ctDNA circulating tumor DNA, EGFR epidermal growth factor receptor, MoAb monoclonal antibodies, MSI microsatellite instability, MT mutated, ORR overall response rate, PD-L1 programmed death-ligand 1, PFS progression-free survival, TGF transforming growth factor, WT wild-type