Findings from a preplanned analysis by mutational status done on data from the FIRE-3 trial, that expanded KRAS testing as a predictive factor of resistance to more rare NRAS gene and BRAF, confirmed previously reported results that first line treatment with FOLFIRI plus the anti-EGFR (epidermal growth factor receptor) agent cetuximab achieve benefit in term of overall response rate and overall survival in most patients with KRAS wild type (exon 2) metastatic colorectal cancer (mCRC), but the benefit encompass also those with wild type KRAS exon 3/4 and wild type NRAS exon 2/3/4. However, a subgroup of patients with mutated RAS did not show similar benefit and achieved improved progression-free survival following treatment with FOLFIRI plus the anti-VEGF (vascular endothelial growth factor) agent bevacizumab.
Dr. Sebastian Stintzing of the Klinikum Grosshadern, University of Munich in Munich, Germany presented results on Saturday, 29 September during the Gastrointestinal Malignancies/Colorectal Cancer Proffered Papers Session (Abstract E17-7073) at the 17th ECCO – 38th ESMO – 32nd ESTRO European Cancer Congress, which was held in Amsterdam, The Netherlands from the 27 September through the 1 October, 2013. The European Cancer Congresses are organised in joint partnership with ESSO, EACR, EONS and SIOPE to offer multidisciplinary and multi-professional educational opportunities in oncology.
Testing for the RAS mutations
The Fire-3 phase III trial (AIO KRK-0306) was conducted at 150 German and Austrian cancer centres as a head to head comparison of FOLFIRI plus either cetuximab or bevacizumab as first-line treatment in patients with metastatic colorectal cancer (mCRC) who had KRAS wild-type disease. Of 752 enrolled patients, KRAS wild-type tumours were confirmed in 592 patients who were then randomised 1:1 to receive first-line FOLFIRI every two weeks plus either cetuximab at 400 mg/m2 on day 1 followed by 250 mg/m2 weekly (arm A) or bevacizumab at 5 mg/kg every 2 weeks (arm B). The results from this overall study population favoured arm A, with cetuximab patients showing median overall survival (OS) nearly four months longer than in the bevacizumab arm.
The results presented at this Congress were from a preplanned analysis that evaluated the effect of KRAS mutations in exon 3 (codon 59/61), exon 4 (codon 117/146)), NRAS exon 2 (cordons 12/13), exon 3 (cordons 59/61) exon 4 (cordons 117/146)) and BRAF (V600E) on the overall response rate (ORR), progression-free survival (PFS) and OS on treatment arms A and B of the FIRE-3 trial. Mutational analyses were done by pyrosequencing in 592 patients who were wild type for KRAS exon 2. A total of 444 (75%) patients had available tumour tissue; of these, sequencing of all RAS mutations was possible in 396 patients.
Greater benefit was demonstrated with FOLFIRI plus cetuximab in the overall intent to treat population of 592 patients with KRAS wild type disease; ORR was 62.0% and 58.0% in arm A and B, respectively (p = 0.183 [Fisher´s one-sided test]). Median OS was 28.7 months with FOLFIRI/cetuximab versus 25.0 months with FOLFIRI/bevacizumab (logrank p = 0.017). Median PFS was similar in both study arms; 10.0 months in arm A versus 10.3 months in arm B (p = 0.547).
Further analysis showed that 301 patients within the wild type RAS subgroup (wild-type KRAS exon 2/3/4 and NRAS exon 2/3/4) showed greater ORR of 76.0% with FOLFIRI/cetuximab over patients who received FOLFIRI/bevacizumab (ORR = 65.2%; Fischer’s one-sided p = 0.026, Fischer’s two-sided p = 0.044). The ORR in 40 patients with mutated BRAF (KRAS exon 2 wild-type and BRAF V600E mutant) was 63.2% versus 42.9%, respectively in arms A and B (p = 0.167). However, the ORRs in 55 patients with mutated RAS (KRAS exon 2 wild-type and KRAS exon 3/4 or NRAS exon 2/3/4 mutant) favoured the comparator arm and were 42.9% and 66.7% in the FOLFIRI plus cetuximab or bevacizumab arms, respectively (p = 0.066).
OS was prolonged with FOLFIRI/cetuximab in RAS wild type patients who achieved 33.1 versus 25.9 months (p = 0.010) in arms A and B, respectively; patients with BRAF mutations experienced OS of 12.9 versus 11.0 months (p = 0.448), respectively. The hazard ratio (HR) for adding cetuximab versus bevacizumab for OS in patients with wild type RAS was 0.69 (p = 0.01). Patients with mutated RAS achieved OS of 19.1 months with cetuximab and 20.6 months with bevacizumab (p = 0.622).
Results for PFS by mutational status showed a similar trend; patients with RAS wild type and BRAF mutation obtained slightly more benefit from FOLFIRI/cetuximab treatment than FOLFIRI/bevacizumab. RAS wild types patients had PFS of 10.5 versus 10.4 months (p = 0.627) and PFS in patients with mutated BRAF was 6.3 and 5.7 months (p = 0.626), respectively. The hazard ratio for PFS in wild type RAS patients was 0.94 (p = 0.63). In patients with RAS mutations, the PFS significantly favoured bevacizumab therapy; PFS was 6.1 months in arm A versus 12.2 months in arm B ( = 0.006).
The authors concluded that these data represent the first phase III findings demonstrating the influence of KRAS exon 3,4 and NRAS exon 2,3,4 mutations on the efficacy of first-line treatment with FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab in patients with mCRC and wild type KRAS (exon 2). Furthermore, they point out the impact that these findings may have on daily clinical decisions since subgroups of patients were identified that were most likely to benefit from the treatment.
The authors presented during the Congress an updated analysis with more patients tested for KRAS exon 3/4, NRAS exon 2/3/4 and BRAF V600E.
Clinical trial information: NCT00433927.
*Loredana Vecchione, ESMO spokeperson who was not involved in the study
The authors state the following conflicts of interest: Research sponsored by Merck and Roche; participation on the Advisory board of Merck, Roche, BMS and travel support from Merck, Roche.