From: KRAS oncogene in non-small cell lung cancer: clinical perspectives on the treatment of an old target
Target | Drug/drug combination | Date | Phase | Patients | Line | KRAS status | Primary endpoint | RR, % | PFS (months) | OS (months) | NCT |
---|---|---|---|---|---|---|---|---|---|---|---|
Farnesyl transferase | Tipifarnib [91] | 2003 | II | 44 | 1 | Unknown | ORR | 0 | 2.7 | 7.7 | NCT00005989 |
Farnesyl transferase | CI-1040 [102] | 2004 | I | 67 | ≥1 | Unknown | ORR | 0 | 4.4 | NA | NCT00033384 |
C-Raf | PD-0325901 [105] | 2010 | II | 34 | ≥1 | Unknown | ORR | 0 | 1.8 | 7.8 | NCT00174369 |
C-Raf | Selumetinib/pemetrexed [107] | 2010 | II | 84 | 2 or 3 | Unknown | Disease progression event | 5 vs 4 | 2.2 vs 3 | NA | NCT00372788 |
Mek | Salirasib [92] | 2011 | II | 33 | All lines | Mut | Rate of nonprogression at 10Â weeks | 0 | TTP: 2 (1st line), 1 (2nd line) | Not reached (1st line), 15 (2nd line) | NCT00531401 |
Mek | Tivantinib + erlotinib/placebo + erlotinib [120] | 2011 | II | 167 | > 1 | Mut, wt, unknown | PFS | 10 vs 7 | 3.8 vs 2.3 | 8.5 vs 6.9 | NCT00777309 |
Mek | RO5126766 [103] | 2012 | I | 52 | All lines | Unknown | Safety | 6.6 | NA | NA | NCT00777309 |
Mek | Cobimetinib + pictilisib [129] | 2012 | Ib | 78 | NS | Unknown | Safety | 14 | NA | NA | NCT00996892 |
Mek | Ridaforolimus [126] | 2012 | II | 79 | > 1 | Mut | PFS | 1 | 4 | 18 | NCT00818675 |
Mek | Tivantinib + erlotinib/placebo + erlotinib [121] | 2012 | III | 1048 | 2 or 3 | Mut, wt, unknown | OS | NS | 3.6 vs 1.9 | 8.5 vs 7.8 | NCT01244191 |
Mek | RO5126766 [104] | 2013 | I | 12 | > 1 | Unknown | Safety | 0 | NA | NA | – |
Mek | Trametinib + docetaxel [113] | 2013 | I/Ib | 46 | > 1 | Mut, wt | Safety | 17 (KRAS-mut: 17) | NA | NA | NCT01192165 |
Proteasome | Trametinib + pemetrexed [116] | 2013 | I/Ib | 42 | > 1 | Mut, wt | Safety | 14.3 (KRAS-mut: 15) | NA | NA | NCT01192165 |
Mek | Trametinib + gemcitabine (2014) | 2013 | Ib | 31 | All lines | Unknown | Safety | 30 | NA | NA | NCT01428427 |
Met | Pimasertib + voxtalisib [130] | 2013 | Ib | 53 | NS | NS | Safety | 7 | NA | NA | NCT01390818 |
Mek | Sorafenib [98] | 2013 | II | 59 | > 1 | Mut | DCR at 6 weeks | 10.5 | 2.3 | 5.3 | NCT00064350 |
Mek | Selumetinib + docetaxel/placebo + docetaxel [109] | 2013 | II | 87 | 2 | Mut | OS | 37 vs 0 | 5.3 vs 2.1 | 9.4 vs 5.2 | NCT00890825 |
Met | Onartuzumab + erlotinib/placebo + erlotinib [122] | 2013 | II | 137 | ≥2 | Mut, wt, unknown | PFS | 5.8 vs 4.4 | 2.2 vs 2.6 | 8.9 vs 7.4 (KRAS-mut: 10.4 vs 7.7) | NCT00854308 |
Met | Ganetespib [137] | 2013 | II | 99 | > 1 | Mut, wt | PFS at 16 weeks | KRAS-mut: 0 | KRAS-mut: 1.9 | KRAS-mut: 11 | NCT01031225 |
mTOR | Copanlisib + refametinib [131] | 2014 | Ib | 49 | NS | Mut, wt, unknown | Safety | 2.2 | NA | NA | NCT01392521 |
Mek, PI3k | Alpelisib + binimetinib [132] | 2014 | Ib | 58 | NS | Mut | Safety | 8.6 | NA | NA | NCT01449058 |
Mek, PI3k | Trametinib/docetaxel [113] | 2015 | II | 129 | 2 | Mut | PFS | 12 vs 12 | 3 vs 2.75 | 2 vs NR | NCT01362296 |
Mek, PI3k | Bortezomib [119] | 2015 | II | 16 | ≥2 | Mut | ORR | 6.6 | 1 | 13 | NCT01833143 |
Fak | Defactinib [134] | 2015 | II | 55 | ≥2 | Mut | PFS at 12 weeks | 1.8 | NA | NA | NCT01951690 |
Hsp90 | Ganetespib + docetaxel/Docetaxel [138] | 2015 | II | 385 | 2 | Mut, wt | PFS | NA | KRAS-mut: 3.9 vs 3.0 | KRAS-mut: 7.6 vs 6.4 | NCT01348126 |
Mek, PI3k, mTOR | Sorafenib/placebo [99] | 2015 | III | 706 | 3 or 4 | Mut, wt | OS | 4.9 vs 0.9 (KRAS-mut: 2.9 vs 0) | 2.8 vs 1.4 (KRAS-mut: 2.6 vs 1.7) | 8.2 vs 8.3 (KRAS-mut: 6.4 vs 5.1) | NCT00863746 |
Mek | Selumentinib + erlotinib/placebo + erlotinib [112] | 2016 | II | 89 | 2 or 3 | Mut, wt | PFS, ORR | 10 vs 0 (mut) | 2.3 vs 4 (mut) | 21.8 vs 10.5 (mut) | NCT01229150 |
Host immunity | Paclitaxel + carboplatin + reolysin [139] | 2016 | II | 37 | ≥1 | Mut, wt | ORR | 31 | 12 | 4 | NCT 00861627 |
Hsp90 | Selumetinib + docetaxel/placebo + docetaxel [111] | 2017 | III | 505 | 2 | Mut | PFS | 20.1 vs 13.7 | 3.9 vs 2.8 | 8.7 vs 7.9 | NCT01933932 |