Exploration of Targeted Anti-tumor Therapy

Table 2. Main clinical trials that explored predictive biomarkers in CRC

Biomarker	Clinical trial	Results
*RAS*	PRIME [15]	The combination of panitumumab and FOLFOX4 significantly improved PFS in patients with KRAS wild-type tumors.
	CRYSTAL [20]	Molecular testing of tumors for all activating RAS mutations is essential before considering anti-epidermal growth factor receptor therapy, thereby allowing the further tailoring of cetuximab administration to maximize patient benefit.
	OPUS [16]	The addition of cetuximab to FOLFOX-4 significantly improved PFS and response in patients with KRAS wild-type tumors.
	MRC COIN [17]	This trial has not confirmed a benefit of addition of cetuximab to oxaliplatin-based chemotherapy in first-line treatment of patients with advanced CRC.
	FIRE-3 [23]	In this study a significantly higher OS was demonstrated for FOLFIRI plus cetuximab compared to FOLFIRI plus bevacizumab in the extended RAS wild-type subgroup.
	NCT03600883 [35]	Early results suggest antitumor activity of single-agent AMG 510 in KRAS^G12C mutant solid tumors.
	NCT03785249 [33]	The trial is ongoing and responses to treatment with MRTX849 have been observed in both lung and CRC KRASG12C mutant patients.
*BRAF*	SWOG 1406 [62]	The addition of vemurafenib to the combination of cetuximab and irinotecan in BRAFV600 mutated tumors resulted in a prolongation of PFS and a higher disease control rate.
*BRAF*	BEACON CRC [63]	A combination of encorafenib, cetuximab, and binimetinib resulted in significantly longer OS and a higher response rate than standard therapy in patients with mCRC with the BRAF V600E mutation.
MSI	NCT01876511 [71]	This study showed that mismatch-repair status predicted clinical benefit of immune checkpoint blockade with pembrolizumab.
MSI	CheckMate 142 [73]	Nivolumab provided durable responses and disease control in pre-treated patients with dMMR/MSI-H mCRC.
HER-2	HERACLES [81]	The combination of trastuzumab and lapatinib is active and well tolerated in treatment-refractory patients with HER2-positive tumors.
HER-2	MyPathway [86]	Durable responses were seen in patients with refractory colorectal cancers with HER2 activation/overexpression when the approved targeted therapy regimen administered without chemotherapy.
CMSs	CALGB/SWOG 80405 [131]	The CMSs are highly prognostic and predictive for OS and PFS.
CMSs	Fire-3(AIO KRK-0306) [132]	Prolonged OS induced by FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab in the FIRE-3 study appears to be driven by CMS2 and CMS4.

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OS: overall survival

Declarations

Author contributions

AMR and NN contributed conception and design of the review; AMR wrote the first draft of the manuscript. All authors contributed to manuscript revision, read and approved the submitted version.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

Not applicable.

Copyright

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