ESMO @ ECC 2013: Phase III FIRE-3 Trial Data Show Most Patients with Wild-Type RAS Metastatic Colorectal Cancer Benefit from First-Line FOLFIRI Plus Cetuximab Treatment

Exclusion of patients with RAS mutations identifies a population which is more likely to benefit from cetuximab.

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.

ESMO Comments bubble

Several independent non-randomised retrospective studies, several retrospective analysis of prospective randomised trials and a European consortium study have largely shown that the presence of KRAS activating mutations in exon 2 correlates with primary resistance to anti-EGFR monoclonal antibodies (moAbs) in metastatic colorectal cancer patients (mCRC). As first reported by De Roock et al, other activating RAS mutations can predict poorer outcome of mCRC patients treated both with cetuximab and panitumumab. In line with the results of the PRIME study, the FIRE-3 trial highlights the importance of better selecting the patients who might benefit from anti-EGFR moAbs by considering other RAS mutations. Moreover, the FIRE 3 study is the first randomised multicentre study that compares in a head to head fashion two biologic agents that are active in mCRC.
In particular, the study compared FOLFIRI plus cetuximab to FOLFIRI plus bevacizumab as first-line treatment in patients with mCRC according to the KRAS exon 2 status. In a pre-planned analysis, the effect of mutations in KRAS exon3 (codon 59/61), exon 4 (codon 117/146)), NRAS (exon 2 (codon 12/13), exon 3 (codon 59/61) exon 4 (codon 117/146)) and BRAF (V600E) on overall response rate (ORR), progression free survival (PFS) and overall survival (OS) was evaluated. The ITT population consisted of 592 KRAS exon 2 wild type (WT) patients with its primary endpoint (ORR) not met (62% for cetuximab/FOLFIRI and 58% for bevacizumab/FOLFIRI, p value: 0.183). No difference in PFS was observed but a statistical significant difference in OS was reported with 28.7 months in the cetuximab group as compared to 25.0 months in the bevacizumab group (p value: 0.017)
In 455 out of 592 patients sequencing of all RAS mutations was possible; 65 out of 455 carry an other RAS mutation while 48 out of 455 carry a BRAF mutation. Patients wild type for KRAS exon 2 and other RAS mutations (defined by the authors as RAS WT) showed higher ORR in the FOLFIRI/cetuximab group as compared to FOLFIRI/bevacizumab.(76.0% vs. 65.2%; Fisher´s p (two-sided): 0.044). There was no statistical significant improvement in PFS (10.5 months in the cetuximab arm versus 10.4 months in bevacizumab arm, p value 0.627) while a better OS was observed. In particular RAS WT patients treated with cetuximab reported 33.1 months of OS as compare to 25.9 months observed in the bevacizumab arm (p value 0.010).
In conclusion, the FIRE-3 is the first head to head study that compares cetuximab plus FOLFIRI to bevacizumab plus FOLFIRI in first line treatment of KRAS exon 2 wild type mCRC. When considering the analysis restricted to the KRAS exon 2 population, no benefit in terms of ORR and PFS was observed. On the contrary, a better OS was reported with 3,5 months gain in the cetuximab group as compared to bevacizumab. Furthermore, this is the first data pertaining the influence of KRAS exon 3,4 and NRAS exon 2,3,4 mutations on treatment efficacy of FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab in first-line treatment of mCRC patients of a phase III randomised study. The results show that the better identification of other RAS mutations can improve both the ORR and the OS in patients receiving cetuximab as compared to bevacizumab. This highlights the importance for detecting other RAS mutations to better select the group of patients who might benefit from anti-EGFR moAbs. These results may have impact on daily clinical decisions as we are able to define a subgroup of patients most likely to benefit from FOLFIRI plus cetuximab in first-line setting.

Loredana Vecchione*

*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.