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Table 1 Strategies to reverse resistance to anti-EGFR mAbs in clinical trials

From: Resistance to anti-EGFR therapies in metastatic colorectal cancer: underlying mechanisms and reversal strategies

Therapy Target Agents Setting Species Subpopulation Treatment regimen Efficiency Reference
New anti-EGFR mAbs EGFR S468R necitumumab Phase II mCRC Unselected Necitumumab plus mFOLFOX6 mPFS:10.0m; mOS:22.5m [21]
EGFR ECD Sym004 Phase I mCRC KRAS WT Sym004 or investigator’s choice mOS: 12.8m VS 7.3m [22]
EGFR-TK Erlotinib Phase II mCRC KRAS WT Erlotinib+ cetuximab ORR:42%; mPFS:5.6m [23]
RAS inhibitors RAS Dasatinib Phase IB/II mCRC KRAS mutation Dasatinib + FOLFOX +cetuximab Not reached [24]
  BRAF Vemurafenib Phase IB mCRC BRAF V600E mutation Vemurafenib + Irinotecan + cetuximab ORR:35%; mPFS:7.7m [25]
RAF inhibitors Phase II mCRC Unselected Vemurafenib+ cetuximab VS cetuximab ORR:0 VS 4%; mPFS3.7 VS 4.5m; mOS:7.1m VS 9.3m [26]
  Encorafenib Phase III mCRC BRAF V600E mutation Encorafenib + binimetinib + cetuximab VS cetuximab chemotherapy ORR: 26% VS 2%, mOS: 9.0m VS 5.4m [27, 28]
MEK inhibitors MEK Binimetinib Phase III mCRC BRAF V600E mutation Encorafenib + binimetinib + cetuximab VS cetuximab chemotherapy ORR: 26% VS 2%, mOS: 9.0m VS 5.4m [28]
Selumetinib Phase I mCRC KRAS mutation Selumetinib + cetuximab Not reached [29, 30]
ERBB2 inhibitors ERBB2 Neratinib Phase II mCRC KRAS, NRAS, BRAF, PIK3CA WT Neratinib + cetuximab Not reached [31]
PI3K inhibitors PI3K PX-866 Phase II mCRC KRAS WT PX-866 + cetuximab VS cetuximab mPFS:59d VS 104d;
mOS:266d VS 333d
[32]
MET inhibitors MET Tivantinib Phase II mCRC KRAS mutation Tivantinib + cetuximab ORR: 9.8%, mPFS: 2.6m,mOS:9.2m [33]
Capmatinib Phase II mCRC MET amplification Capmatinib + gefitinib ORR: 47% [34]
IGF-1R inhibitors IGF-1R Dalotuzumab Phase II/III mCRC KRAS WT Dalotuzumab + Irinotecan + cetuximab VS placebo + Irinotecan + cetuximab mPFS: 5.4m VS 5.6m;mOS:11.6 VS 14.0m [35]
IMC-A12 Phase II mCRC Unselected IMC-A12 + cetuximab VS IMC-A12 Non response [36]
Metabolic regulators SGLT2 Dapagliflozin Case report mCRC SGLT2+ Dapagliflozin + cetuximab CEA dropped and tumor regression [37]
Immune checkpoint inhibitors PD-L1 Avelumab Phase II mCRC RAS WT Avelumab + cetuximab mPFS:3.6m; mOS:11.6m [38]
Antiangiogenic agents VEGFR Regorafenib Phase I mCRC At least 4-line treatment Regorafenib + cetuximab PR:1/17; SD: 7/17 [39]