Background
Historical overview
KRAS biology
KRAS mutations as a prognostic factor
Reference | Type of study | Patients tested for KRAS | Patients by KRAS status | Results (KRAS-mut vs KRAS-wt) | |
---|---|---|---|---|---|
KRAS-mut | KRAS-wt | ||||
Mascaux et al., 2005 [61] | Pooled analysis | 3620 (stage I-IV) | 652 | 2968 | HR for OS 1.35 (1.16–1.56), p = 0.01 |
Sheperd et al., 2013 [62] | Pooled analysis | 1543 (stage I-III) | 300 | 1246 | HR for OS 1.17, 95% CI 0.96 to 1.42, p = 0.12 |
Zer et al., 2016 [63] | Pooled analysis | 577 (stage IIIB-IV) | 120 | 457 | HR for OS 1.09, 95% CI 0.85–1.41, p = 0.48 |
Pan et al., 2016 [64] | Pooled analysis | 13,103 (stage I-IV) | 2374 | 10,729 | HR for OS 1.56, 95% CI 1.39–1.76, p = 0.00 |
Svaton et al., 2016 [66] | Individual study | 129 (stage IIIB-IV) | 39 | 90 | OS: 16.1 months for wt-KRAS and 7.2 for mut-KRAS |
PFS: 2.3 for wt-KRAS and 1.6 for mut-KRAS | |||||
Fan et al., 2017 [65] | Pooled analysis | 658 (advanced NSCLC) | 93 | 565 | HR for PFS 1.83, 95% CI 1.40–2.40, p < 0.0001 |
693 (advanced NSCLC) | 106 | 587 | HR for OS 2.07, 95% CI 1.54–2.78, p < 0.0001 |
KRAS mutations as a predictive factor
Predictive value of KRAS mutations for response to chemotherapy
Reference | Patients tested for KRAS | Patients by KRAS status | Treatment arm | Endpoint | KRAS-mut | KRAS-wt | |
---|---|---|---|---|---|---|---|
KRAS-mut | KRAS-wt | ||||||
Rodenhius et al., 1997 [68] | 62 (stage III-IV) | 16 | 46 | Carboplatin + ifosfamide + etoposide | ORR (%) | 19 | 26 |
PFS (months) | 4 | 5 | |||||
OS (months) | 8 | 9 | |||||
Schiller et al., 2001 [69] | 184 (stage II-IIIA) | 44 | 140 | Cisplatin + etoposide | OS (months) | 24.7 | 42 |
Eberhard et al., 2005 [70] | 133 (advanced stage) | 25 | 108 | Carboplatin + paclitaxel + erlotinib | ORR (%) | 23 | 26 |
PFS (months) | 6.0 | 5.4 | |||||
OS (months) | 13.5 | 11.3 | |||||
Tsao et al., 2007 [71] | 210 (stage Ib-II) | 46 | 164 | Vinorelbine + cisplatin | OS (months) | 6.4 | NR |
Mao et al., 2010 [76] | 1470 (stage NS) | 231 | 1239 | EGFR TKI | ORR (%) | 3 | 26 |
Khambata-Ford et al., 2010 [82] | 202 (stage IIIB, IV) | 35 | 167 | Taxane + carboplatin + cetuximab | ORR (%) | 30.8 | 32.9 |
PFS (months) | 5.6 | 5.1 | |||||
OS (months) | 16.8 | 9.7 | |||||
O’Byrne KJ et al., 2011 [83] | 395 (stage IIIB, IV) | 75 | 320 | Cisplatin + vinorelbine + cetuximab | ORR (%) | 36.8 | 37.3 |
PFS (months) | 5.4 | 4.4 | |||||
OS (months) | 8.9 | 11.4 | |||||
Ludovini V et al., 2011 [79] | 166 (stage III, IV) | 11 | 151 | EGFR TKI | ORR (%) | 0 | 35.7 |
PFS (months) | 2.7 | 5.6 | |||||
OS (months) | 19.3 | 28.6 | |||||
Metro et al., 2012 [81] | 67 (stage IIIB-IV) | 18 | 49 | EGFR TKI (gefitinib or erlotinib) | PFS (months) | 1.6 | 3.0 |
OS (months) | 6.0 | 21.0 | |||||
Fiala O et al., 2013 [80] | 448 (stage IIIB, IV) | 138 (G12C mutation: 38) | 410 | EGFR TKI | PFS (weeks) | 4.3 (G12C) vs 9.0 (non-G12C) | |
OS (weeks) | 12.1 (G12C) vs 9.3 (non-G12C) | ||||||
Zer et al., 2016 [63] | 785 (stage IIIB-IV) | 155 | 630 | EGFR TKI (pooled analysis) | OS (months) | 4.5 | 6.0 |
Hames ML et al., 2016 [73] | 150 (stage IV) | 80 | 70 | Conventional chemotherapy | PFS (months) | 4.5 | 5.7 |
OS (months) | 8.8 | 13.5 | |||||
Dong ZY et al., 2017 [84] | 34 (not specified) | 8 | 26 | Pembrolizumab | ORR (%) | 25 | 6.6 |
20 (not specified) | 5 | 15 | Pembrolizumab or nivolumab | PFS (months) | 14.7 | 3.5 |
Predictive value of KRAS mutations for response to targeted therapy
Targeted therapies for KRAS-mutant lung cancer
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 10 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 |