Mutations within the EGFR signaling pathway: Influence on efficacy in FIRE-3—A randomized phase III study of FOLFIRI plus cetuximab or bevacizumab as first-line treatment for wild-type (WT) KRAS (exon 2) metastatic colorectal cancer (mCRC) patients.

Abstract

445 Background: The FIRE-3 study (AIO KRK-0306) was designed as a randomized multicenter trial to compare the efficacy of FOLFIRI plus cetuximab (cet) to FOLFIRI plus bevacizumab (bev) as first-line treatment in KRAS WT mCRC patients. FOLFIRI plus cet as first-line treatment of KRAS WT mCRC patients resulted in comparable overall response rates (ORR) and progression free survival (PFS) when compared to FOLFIRI plus bev. Overall survival (OS) was significantly longer in the FOLFIRI plus cet arm. Methods: In a preplanned analysis, the effect of mutations within the EGFR dependent pathway were investigated. Next to mutations within KRAS (exon 2, 3, 4), NRAS (exon 2, 3, 4) and BRAF (V600E), mutations within PIK3CA (exon 9 and 20) and Akt were investigated and their impact on ORR, PFS and OS within the FIRE-3 population was evaluated. The analysis of all mutations was carried out employing pyrosequencing. Results: The ITT population consisted of 592 KRAS WT (exon 2) patients. The current analysis includes 488 cases (82.4%) with tumor tissue available. In 407 pts sequencing of all RAS mutations was possible. The ORR within the WT RAS patient group was higher in the FOLFIRI plus cet arm (65.5% vs 59.6%; Fisher´s p: 0.157). HRs (cet; bev) for pts with WT RASwere 0.93 (95% CI, 0.74-1.17; p = 0.54) for PFS and 0.70 (95% CI, 0.53-0.92; p = 0.01) for OS. PIK3CA mutation did not influence PFS nor OS when compared to the RAS wt population. Conclusions: ORR and OS were increased in patients with cet plus FOLFIRI as compared to bev plus FOLFIRI in patients without RAS mutations. Exclusion of patients with RAS mutations identifies a population which is more likely to benefit from cetuximab. Clinical trial information: NCT00433927.

Molecular Prognostic Factors in Gastric Cancer

“…Recent data have revealed HER2 overexpression in 7-34% of patients with gastroesophageal adenocarcinomas and an eiciency of anti-HER2 therapies for both in vitro and in vivo gastric cancer models [97].…”

Potentially resectable metastatic colorectal cancer: An individualized approach to conversion therapy

“…On the contrary, all-RAS wild type patients show a significant improvement in both OS and PFS. Similarly, ORR is improved in all-RAS wild type patients treated with anti-EGFR MoAb therapy, making a deeper molecular screening crucial in the context of a conversion therapy [ [25], [70], [71], [72], [73], [74]]. …”

Heterogeneity in the colorectal primary tumor and the synchronous resected liver metastases prior to and after treatment with an anti-EGFR monoclonal antibody

“…are not yet available, mutations in exons 2, 3 and 4 of the Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) and neuroblastoma RAS viral oncogene homolog (NRAS) genes are predictive of resistance to anti-EGFR mAbs, whereas the Val600èGln (V600E) mutation of the B-Raf proto-oncogene (BRAF) has a strong prognostic role, predicting resistance to standard CT (2)(3)(4)(5)(6). Therefore, mutations in the RAS and BRAF genes may identify subgroups of tumors with specific biological, pathological and clinical features, a phenomenon referred to as 'inter-tumor heterogeneity'.…”