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 KRASG12C 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.
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.
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.
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.
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.

OS: overall survival