Setting Irinotecan- refractory Refractory disease to 5-FU and Irinotecan Treatment Cetuximab monotherapy Cetuximab monotherapy vs. Cetuximab + Irinotecan Refractory disease to 5-FU, Cetuximab Irinotecan, and monotherapy Oxaliplatin Cetuximab + Irinotecan + 5-FU/FA Cetuximab monotherapy vs. BSC Cetuximab + FOLFOX-4 Cetuximab + Irinotecan vs. Irinotecan Cetuximab + FOLFIRI vs. FOLFIRI Panitumumab monotherapy versus BSC Irinotecan + Cetuximab+ Bevacizumab vs. Cetuximab + Bevacizumab Cetuximab + Bevacizumab + Irinotecan Single Arm phase II [15] First-line treatment Refractory disease to 5-FU, Irinotecan and Oxaliplatin First-line treatment Refractory to Oxaliplatin Refractory disease to 5-FU, Irinotecan and Oxaliplatin Randomized phase III [19] First-line treatment Randomized phase II [21] Refractory to Irinotecan Single Arm phase II [22] Refractory to Irinotecan + Bevacizumab Table 1: Clinical trials of antiEGFR monoclonal antibodies in metastatic CRC. No. of patients ORR (%) mTTP (mos) mPFS (mos) mOS (mos) 111 vs. 218 10.8∗ vs. 22.9 1.5∗ vs. 4.1 1.4 1.4 9.9 N.R. N.R. N.R. N.R. N.R. Pathology Research International N.R. N.R. N.R. N.R. 12.3 N.R. N.R. 6.4 6.9 vs. 8.6 6.6 33.0 30 6.5 vs. 6.5 14.5 vs. 11.4 10.6 57 346 21 43 9 12.4 67 8∗ vs. 0 72 287 vs. 285 1.9∗ vs. 1.8 6.1∗ vs. 4.6 648 vs. 650 16.4∗ vs. 4.2 4.0∗ vs. 2.6 10.7 vs. 10.0 602 vs. 600 46.9∗ vs. 38.7 8.9∗ vs. 8.0 N.R. 231 vs. 232 10.0∗ vs. 0 8 weeks∗ vs. 7.3 weeks 4 Study Single Arm phase II [12] Randomized phase II [13] Single Arm phase II [14] Randomized phase III [16] Single Arm phase II [17] Randomized phase III [18] Randomized phase III [20] 43 vs. 40 37 vs. 20 7.3 vs. 4.9 33 9 3.9 ∗ Statistically signiﬁcant improvement. ORR: overall response rate; mTTP: median time to progression; mPFS: median progression-free survival; mOS: median overall survival; N.R.: not reported; 5-FU: 5-ﬂuorouracil; BSC: best supportive care; FA: folinic acid; NS: not signiﬁcant. CRC. This mutation was found in 15% of the patients and was associated with a lack of response to therapy (0% versus 32%, P = .016) and a shorter overall survival (4.1 months versus 13.9 months, P = .037) [61]. An additional retrospective analysis of 113 patients treated with antiEGFR monoclonal antibodies found the V600E BRAF mutation in 14% of the KRAS WT patients and was associated with no response to therapy and a statistically signiﬁcant shorter progression-free survival and overall survival compared with BRAF WT patients [59]. In De Roock’s retrospective analysis of tumor samples from patients treated with cetuximab plus chemotherapy, a BRAF mutation was discovered in 4.7% of tumors [26]. In KRAS wild types, carriers of BRAF mutations had a signiﬁcantly lower response rate to cetuximab than in BRAF wild types (8.3% versus 38.0%, P = .0012), a signiﬁcantly shorter PFS (8 versus 26 weeks, P < .0001), and a signiﬁcantly shorter OS (26 versus 54 weeks, P < .0001) [26]. KRAS and BRAF mutation status do not, however, appear to aﬀect the clinical beneﬁt of oxaliplatin or irinotecan on PFS or OS [62]. Several compounds (PLX4032, PLX4720, and GDC-0879) which selectively inhibit the kinase enzyme BRAF containing the V600E mutation are in clinical development [63]. In BRAF mutant cancer cell lines, these selective BRAF inhibitors potently block RAF-MEK- ERK signaling. However, in those tumors that are BRAF WT, but possess a KRAS mutation, these BRAF inhibitors activate this same pathway and therefore should be avoided in those cancers with RAS mutations [64–66].