Table 1.
Summary of the targeted agents and clinical trials to overcome resistance to EGFR-TKI
| Target | classification | Agents | Clinical trials finished | Clinical trials ongoing |
|---|---|---|---|---|
| T790M | Covalent EGFR-TKI inhibitor | Afatinib | LUX-lung 1 [78], LUX-lung 2 [163], LUX-lung 3 [80], LUX-lung 4 [79], LUX-lung 6 [81] | NCT01085136, NCT01466660, NCT01523587 |
| T790M-selective inhibitor | CO-1686, PKC412, AZD9291 | Phase I studies of PKC412 [89,164] | NCT01526928, NCT02147990 (TIGER-2), NCT01802632 (AURA), NCT02094261 (AURA2) | |
| HGF | HGF antagonist | NK4 | ||
| Anti-HGF antibody | TAK-701, ficlatuzumab | Phase I study of TAK 701 [94] | NCT01039948 | |
| Phase II trial comparing gefitinib with and without ficlatuzumab [165] | ||||
| MET | MET tyrosine kinase inhibitors | Tivantinib, cabozantinib, INC280 | Phase II study comparing erlotinib with or without tivantinib [97] | NCT01580735, NCT02049060, NCT01377376, NCT00596648, NCT01866410, NCT01639508, NCT01610336 |
| Phase III study comparing erlotinib with and without tivantinib [29] | ||||
| MET mono-antibody | Onartuzumab | phase II trial comparing erlotinib with and without onartuzumab [166] | NCT01456325 (MetLung) NCT01887886, NCT02031744 | |
| HER3 | Anti-HER3 agents | Pertuzumab | Phase II study exploring pertuzumab plus erlotinib [107] | |
| HER2 | Anti-HER2 agents | Lapatinib, trastuzumab, neratinib | Phase II trial evaluating lapatinib as monotherapy [167] | NCT01827267, NCT01184482, NCT01306045, NCT00004883, NCT00758134, NCT01827267, NCT00266877 |
| Phase II trial evaluating neratinib [168] | ||||
| IGF-1R | IGF-1R mono-antibody | R1507 | Phase II study exploring erlotinib plus placebo or R1507 [169] | NCT00773383 |
| PI3K | PI3K inhibitors | BAY 80-6946, LY294002 | NCT01460537, NCT01411410, NCT01404390, NCT00962611 | |
| mTOR | mTORC1 inhibitors | Everolimus, temsirolimus, sirolimus | Phase II exploring everolimus plus gefitinib [111] | NCT00079235, NCT01827267, NCT01737502, NCT01050985, NCT01482156 |
| Phase II study of temsirolimus monotherapy [170] | ||||
| Dual PI3K/mTOR inhibitors | BEZ235, PF-04691502, PKI-402 | Phase I study of PF-04691502 monotherapy [122] | NCT01482156, NCT00620594, NCT01343498, NCT01508104 | |
| AKT | AKT inhibitors | MK-2206, Enzastaurin, | Phase I trial exploring MK-2206 plus carboplatin/paclitaxel, docetaxel or erlotinib [124] | NCT01147211, NCT01294306, NCT00452413 |
| Phase I trials exploring enzastaurin plus gemcitabine/cisplatinin [126] | ||||
| Phase II study, exploring enzastaurin plus cisplatin/pemetrexed [127] | ||||
| HSP90 | Hsp90 inhibitors | Ganetespib, AUY-922, DS-2248, retaspimycin, 17-DMAG | Phase II study evaluating IPI-504 monotherapy [140] | NCT01348126, NCT01031225, NCT01259089, NCT01784640, NCT01288430, NCT01362400, NCT01427946 |
| Phase II study evaluating ganetespib monotherapy [141] |