In KRAS wild-type patients, BEV addition to doublet chemotherapy significantly increased ORR, PFS and OS up to 60% to 61%, 10.5 to 13.5 months and 21.8 to 27.7 months, respectively [18, 21, 31, 32]. Randomized studies of anti-EGFR added to doublets, in EGFR-overexpressing patients, reported ORR 50% to 61%, PFS 7.7 to 10.6 months, OS 22.4 to 24.9 months [22, 23, 31–33]. First-line cetuximab plus FOLFOX4, significantly improved ORR and PFS in KRAS/BRAF wild-type population, similarly to KRAS wild-type patients . In KRAS mutant patients, BEV addition to doublet chemotherapy (IFL) significantly increased median PFS up to 9.3 months, while ORR was equivalent to doublet arm (43.2% and 41.2%, respectively), and median OS increased up to 19.9 months, even if not significantly [21, 35].
In KRAS wild-type and mutant MCRC patients, BEV addition to triplet chemotherapy, according to FIr-B/FOx schedule, reported high activity and efficacy: ORR 90% and 67%, median PFS 14 and 11 months, median OS 38 and 20 months, respectively. A similar clinical outcome was also obtained in KRAS/BRAF wild-type patients. Equivalent efficacy was reported with FOLFOXIRI/BEV regimen: ORR 82% and 71%, median PFS 13.6 and 12.6 months, respectively . In unresectable colorectal liver metastases, ORR 79%, median PFS 14 months, median OS 37 months were reported with chrono-IFLO/cetuximab .
Median PFS and OS values of MCRC patients treated with FIr-B/FOx were different in KRAS wild-type and mutant patients, even if not significantly, while they were equivalent in the FOLFOXIRI plus BEV study . BEV addition to doublet IFL chemotherapy gave median PFS 13.5 and 9.3 months, median OS 27.7 and 19.9 months in KRAS wild-type and mutant patients, respectively [18, 21]. Significantly better prognosis was reported in KRAS/BRAF wild-type patients compared with patients harboring mutations in the KRAS or BRAF genes (HR 0.51) . Direct comparison of OS between KRAS wild-type and mutant MCRC patients treated with BEV-containing chemotherapy failed to significantly differentiate prognosis, as in the present study. Thus, intensive regimens adding BEV to triplet chemotherapy can further increase activity and efficacy in KRAS wild-type and mutant patients. Randomized studies would be able to properly evaluate this.
The high activity of triplet chemotherapy plus BEV regimens correlated with increased resection rate of liver metastases and pathologic CR, particularly in L-L MCRC patients [1, 3, 4, 6]. We recently reported that the clinical outcome of L-L compared to multiple metastatic disease was significantly improved up to median PFS 17 months and median OS 44 months  due to the effectiveness of integrated FIr-B/FOx intensive treatment and secondary liver surgery. The present analysis confirms the significantly favorable prognosis of L-L compared to MM patients and show that KRAS wild-type L-L patients, accounting for 20% of fit MCRC patients, could gain 100% overall activity with an integrated medical and surgical approach, due to performed liver metastasectomies and long-lasting cCRs; median PFS 21 months and OS 47 months. A significantly favorable prognosis was demonstrated in KRAS wild-type L-L compared to O/MM patients, even if this represents a retrospective, exploratory analysis in a small cohort of MCRC patients. Using neoadjuvant cetuximab with either FOLFOX6 or FOLFIRI for unresectable colorectal liver metastases, metastasectomies were performed in 38% and 30% patients, respectively . Chrono-IFLO/cetuximab reported a 60% R0 resection rate in unresectable colorectal liver metastases, with ORR 79%, median PFS 14 months and median OS 37 months . Further prospective studies will properly address whether intensive medical treatments, such as FIr-B/FOx, and secondary liver surgery could represent the standard multidisciplinary strategy for KRAS wild-type L-L MCRC patients. In KRAS mutant patients, prevalently harboring c.35 G>A transversion (53.5%), integrated medical and surgical treatment failed to significantly increase PFS and OS in L-L compared to O/MM patients: median PFS was equivalent (11 months), in spite of 54% performed liver metastasectomies in L-L patients; median OS was 39 and 19 months, respectively. These data should be further evaluated in a larger cohort of MCRC patients. A proper multidisciplinary treatment strategy for KRAS mutant patients, showing different aggressiveness , sensitivity to medical treatment, and worse clinical behavior, is an unmet need.