Table 2.
Tumor KRAS mutations and outcome of panitumumab- or cetuximab-based treatment in patients with metastatic colorectal cancer*
| First author(reference) | Treatment [type of study; type of patients] | No. of patients with KRAS mutation/total No. of patients (%) | Outcome by KRAS status, No. of patients (%)† |
Association of KRAS mutation with response and survival parameters | |||||
| Complete or partial response |
Stable disease |
Progressive disease |
|||||||
| MT | WT | MT | WT | MT | WT | ||||
| Monotherapy | |||||||||
| Amado (27)‡* | Panitumumab, [phase III, chemotherapy refractory] | 84/208 (40) | 0/84 (0) | 21/124 (17) | 10 (12) | 42 (34) | 59 (70) | 45 (36) | KRAS mutation associated with shorter PFS vs wild type (7.4 vs 12.3 wk): no benefit of panitumumab vs BSC in this subgroup |
| Amado (27)§ | Panitumumab crossover [phase III extension, chemotherapy refractory] | 77/168 (46) | 0/77 (0) | 20/91 (22) | 20 (26) | 35 (38) | 37 (48) | 23 (25) | |
| Freeman (36) | Panitumumab [patient cohort, chemotherapy refractory] | 24/62 (39) | 0/24 (0) | 4/38 (11) | 5 (21) | 20 (53) | 19 (79) | 14 (37) | Median PFS = 7.4 wk for MT KRAS vs 16.2 wk for WT. Median OS = 22.2 wk for MT KRAS vs 42.9 wk for WT |
| Karapetis (55) | Cetuximab [phase III, chemotherapy refractory] | 81/198 (41) | 1/81 (1) | 15/117 (13) | NA | NA | NA | NA | KRAS mutation associated with shorter PFS and OS vs WT (P < .001 for both) |
| Khambata-Ford (59)* | Cetuximab [NA, chemotherapy refractory] | 30/80 (38) | 0/30 (0) | 5/50 (10) | 3 (10) | 19 (38) | 27 (90) | 26 (52) | KRAS mutations found in three (11%) DC vs 27 (51%) NR (P < .001) and associated with lower DC rate (10% vs 48%; P < .001) but similar PFS (59 vs 61 d) |
| Mainly combination therapy | |||||||||
| Benvenuti (33) | Cetuximab ± CT or panitumumab [patient cohort, chemotherapy naïve and refractory] | 16/48 (33) | 1/16 (6) | 10/32 (31) | 5 (31) | 8 (25) | 10 (63) | 14 (44) | KRAS/BRAF mutation negatively associated with PR (P < .01). KRAS mutation associated with shorter TTP (P = .04) |
| De Roock (57) | Cetuximab ± CT [patient cohort, chemotherapy refractory] | 42/108 (39) | 0/42 (0) | 27/66 (41) | 31 (74) | 28 (42) | 11 (26) | 11 (17) | KRAS mutation found in 0% of OR vs 52% of NR (P < .001) and associated with shorter OS (27.3 vs 43.0 wk (P = .02) |
| Di Fiore (56) | Cetuximab + CT [patient cohort, chemotherapy refractory] | 22/59 (37) | 0/22 (0) | 12/37 (32) | 5 (23) | 14 (38) | 17 (77) | 11 (30) | KRAS mutation was associated with PD (P < .001) and shorter TTP (3 vs 5.5 mo; P < .01) |
| Lievre (34) | Cetuximab ± CT [patient cohort, chemotherapy naïve and refractory] | 13/30 (43) | 0/13 (0) | 11/17 (65) | 4 (31) | 2 (12) | 9 (69) | 4 (24) | KRAS mutation associated with shorter OS (6.9 vs 16.3 mo; P = .02) |
| Lievre (60) | Cetuximab + CT [patient cohort, chemotherapy refractory] | 24/89 (27) | 0/24 (0) | 26/65 (40) | NA | NA | NA | NA | KRAS mutation associated with shorter PFS (10.1 vs 31.4 wk; P < .001) and OS (10.1 vs 14.3 mo; P = .03) |
| Combination with chemotherapy (first-line setting) | |||||||||
| Bokemeyer (28) | FOLFOX [phase II, chemotherapy naïve] | 47/233 (20) | 23/47 (49) | 27/73 (37) | 17/47 (36) | 30/73 (41) | 5/47 (11) | 12/73 (16) | Median PFS = 8.6 vs 7.2 mo in MT and WT patients, respectively |
| FOLFOX + cetuximab [phase II, chemotherapy naïve] | 52/233 (22) | 17/52 (33) | 37/61 (61) | 27/52 (52) | 19/61 (31) | 7/52 (13) | 3/61 (5) | No benefit of adding cetuximab to FOLFOX in KRAS MT patients, median PFS = 5.5 vs 7.7 mo in MT and WT patients, respectively | |
| Van Cutsem (29) | FOLFIRI [phase III, chemotherapy naïve] | 87/263 (33) | (40) | (43) | (46) | (44) | NA | NA | Median PFS = 8.1 vs 8.7 mo in MT and WT patients, respectively; median OS = 17.7 vs 21.0 mo in MT and WT patients, respectively |
| FOLFIRI + cetuximab [phase III, chemotherapy naïve] | 105/277 (38) | (36) | (59) | (47) | (31) | NA | NA | No benefit of adding cetuximab to FOLFIRI in KRAS MT patients, median PFS = 7.6 vs 9.9 mo in MT and WT patients, respectively; median OS = 17.5 vs 24.9 mo in MT and WT patients, respectively | |
Studies that prospectively evaluated biomarkers. BSC = best supportive care; CR = complete response; CT = chemotherapy; DC = disease control (PR or SD); FOLFIRI = folinic acid, fluorouracil, and irinotecan; FOLFOX = folinic acid, fluorouracil, and oxaliplatin; MT = mutant; NA = not available; NR = nonresponse or nonresponder; OR = objective response or responder; OS = overall survival; PD = progressive disease; PFS = progression-free interval; PR = partial response or responder; SD = stable disease; TTP = time to disease progression; WT = wild type.
Expressed as a percentage of patients within the MT and WT subgroup. (the denominator is also shown in the first two columns).
Phase III comparison of panitumumab vs BSC (data for panitumumab recipients only are shown).
Patients initially assigned to BSC who crossed over to panitumumab treatment after disease progression in the phase III study.