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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]