Here, we utilise the open-label, randomised phase III trial (FIRE-3, AIO KRK-0306) in metastatic colorectal carcinoma patients, who received either cetuximab or bevacizumab in combination with 5-fluorouracil, folinic acid and irinotecan (FOLFIRI)....KRAS mutated tumours classified as CMS1 tended to show a longer OS compared to wild-type tumours when treated with bevacizumab...In particular, treatment response differed for tumours classified as CMS4 by KRAS status, showing better response for cetuximab in KRAS wild-type and for bevacizumab in KRAS mutated tumours, respectively.

...- KRAS wild-type and KRAS mutant patients are eligible...

...RAS mutation (including KRAS, NRAS and HRAS); 5. ...

...-Histologically proven diagnosis of colorectal cancer -Mutation Status KRAS -No previous first line chemoterapy treatment - Written informed consent....

...Overall Survival (OS) in Participants With mCRC and a Documented KRAS Mutation who Received Bevacizumab-Containing Treatment or Chemotherapy Alone in Routine Clinical Practice...

...An ARMS-PCR proven KRAS, NRAS mutation, excluding BRAF mutation or microsatellite instablility-High; 3....

...Wild-type or mutated KRAS tumor status....

...Tumor tissue available for determination of KRAS mutational status. ...

...Progression-free survival: native versus mutated K-RAS; tumour assessments according to RECIST criteria...

...- Tumor tissue available for determination of KRAS mutational status...

...Overall survival`Overall response rate`Time to onset of response`Duration of response`Treatment cycles number`Number of patients who need medicine dose reduction`adverse events`Prognostic and predictive factor of Circulating endothelial cells (CEC) and circulating tumors cells (CTC) baseline and after 3 cycle`Prognostic factor of the K-Ras gene mutation...

...Examine the influence of a potential predictive and prognostic tumour biomarker -mutations in K-RAS- after start of therapy on overall objective response`Examine the influence of a potential predictive and prognostic tumour biomarker -mutations in K-RAS- after start of therapy on surgical resection rate`Examine the influence of a potential predictive and prognostic tumour biomarker -mutations in K-RAS- after start of therapy on survival`Examine the influence of a potential predictive and prognostic tumour biomarker -mutations in K-RAS- after start of therapy on progression free survival...

Forty-two patients were enrolled. Median age was 67 years (range 41–79 years), 44% were male, 100% had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–1, 85% were KRAS and 15% NRAS mutant...DCR was 57.1% (90% CI, 44.6 %-69.3%, P = 0.0690), respectively. The median progression-free survival (PFS) was 4.6 months...FTD/TPI is an important therapeutic resource in refractory RAS mutated metastatic colorectal cancer that combines manageability and safety.

Therefore, this study aimed to carry out a biomarker analysis by liquid biopsy using updated data of the phase II trial of FOLFOXIRI plus bevacizumab as first-line chemotherapy for RAS-mutant mCRC. The levels of circulating tumour DNA (ctDNA) and specific KRAS and NRAS variants were evaluated using real-time PCR assays. ORR was 75.8% (95% confidence interval 65.1% to 86.5%). The median progression-free survival was 12.1 months, and the median overall survival (OS) was 30.2 months. Survival analysis indicated that the median OS from progression was significantly longer in patients with RAS mutation clearance than in those with RAS mutation in the ctDNA at disease progression (15.1 versus 7.3 months, hazard ratio: 0.21, P = 0.0046).

We aimed to investigate the differences in efficacy and safety between bevacizumab combined with capecitabine maintenance therapy and capecitabine monotherapy for RAS-mutant mCRC（as defined by mutations in KRAS and NRAS exons 2-4）controlled by bevacizumab plus FOLFIRI chemotherapy for at least 12 weeks. All patients were first treated with bevacizumab combined with FOLFIRI for at least 12 weeks of induction therapy. 78 patients were in the observation group (bevacizumab plus capecitabine) and 76 patients were in the control group (capecitabine alone). The median progression-free survival (mPFS)of patients was 9.0 months (95% CI 8.0-10.0) in the observation group and 7.2 months (95% CI 6.0-8.4) in the control group, with a statistically significant difference (p < 0.05). Bevacizumab combined with capecitabine was well tolerated and contributed to a longer PFS time than capecitabine alone...

This multicenter phase II trial aimed to examine the efficacy and safety of bevacizumab plus mFOLFOX6 for advanced CRLMs harboring mutant-type KRAS….The rates of complete and partial responses were 0% and 62.1%, respectively….During the median follow-up of 30.7 months, the 3-year OS rate for all the patients was 64.4% with the median survival of 49.1 months....For advanced CRLMs harboring mutant-type KRAS, bevacizumab plus mFOLFOX6 achieved a high R0 resection rate, leading to favorable survival.

RAS and BRAF mutation rates were found to be 36% and 39%, respectively. As first-line therapy, 196 (54%) patients received bevacizumab and Anti-EGFR treatments in combination with chemotherapy….Objective response rate was 42% (n = 152) and 32% (n = 78) for 1st line and 2nd line treatments, respectively. While the median progression free survival (PFS) with the 1st line treatment was 10 months, it was 7 months with the 2nd line treatments. In the total study population median PFS and overall survival (OS) were 10 (95% CI, 8.3 - 11.6) and 35 (95% CI, 30.7 - 39.2) months, respectively.... it was found that wild RAS and BRAF mutations and second metastasectomy contributed to overall survival (p = 0.047 and p < 0.001).

Patients who had advanced CRLMs (tumor number of ≥5 and/or technically unresectable) harboring mutant-type KRAS were included in this study. The induction chemotherapy of bevacizumab plus mFOLFOX6 was administered and assessed for resectability every 4 cycles. The rates of complete and partial responses were 0% and 62.1%, respectively. R0 and R1 resections were performed in 19 and 1 patient, respectively (R0 resection rate: 65.5%). The 3-year PFS and OS rates were 7.4%, and 64.4%, respectively. The 3-year RFS rate was 10.0% in 20 patients who achieved R0 or R1 resections. Bevacizumab plus mFOLFOX6 achieved a high R0 resection rate with a favorable survival for patients with advanced CRLMs harboring mutant-type KRAS.

PRODIGE 14 was an open-label, multicenter, randomised Phase 2 trial. CRC patients with initially defined unresectable liver-only metastases received either, 2-CTx (FOLFOX or FOLFIRI) or 3-CTx (FOLFIRINOX), plus bevacizumab/cetuximab by RAS status. We failed to increase from 50 to 70% the R0/R1 liver-resection rate with the use of 3-CTx combined with bevacizumab or cetuximab by RAS status in CRC patients with initially unresectable liver metastases.

For patients with initially unresectable RAS mutant colorectal liver metastases, bevacizumab combined with mFOLFOX6 increased the resectability of liver metastases and improved response rates and survival compared with mFOLFOX6 alone.

Between May 2012 and March 2015, 232 patients, mostly with RAS (65%) or BRAF (9%) mutant tumours, were randomised in 16 Italian centres....The activity of FOLFOXIRI plus bevacizumab is confirmed in a population with high prevalence of RAS/BRAF mutations treated with a 4-months induction.

CONTRADICTING EVIDENCE: Median PFS was significantly longer in KRAS wt patients compared with that in KRAS mut patients (HR = 0.85; 95 % confidence interval (CI) 0.74-0.98; P = 0.02). Similarly, median OS was significantly better in wt KRAS patients compared with that in mut KRAS patients (HR = 0.65; 95 % CI 0.46-0.92; P = 0.01).