Association of K-ras Mutational Status and Clinical Outcomes in Patients with Metastatic Colorectal Cancer Receiving Panitumumab Alone

A stable IgG-like bispecific antibody targeting the epidermal growth factor receptor and the type I insulin-like growth factor receptor demonstrates superior anti-tumor activity

“…Notably, the response of tumor cell lines to EI-04 was independent of their mutation status in K-Ras, a predictive biomarker for clinical resistance to EGFR mAb-based therapy in metastatic colorectal carcinoma. 28,29 Our data suggests that EI-04 BsAb has potential utility in treating expanded patient populations compared with EGFR mAbs and may overcome tumor resistance to single EGFR mAb treatment.…”

“…Clinically, EGFR inhibitors are known to be efficacious in only a subpopulation of cancer patients, and intense research for molecular predictors of clinical outcomes to EGFR targeted therapies has identified K-Ras mutation as a predictive biomarker of resistance to EGFR mAbs treatment in colorectal cancer and EGFR gene mutation or high copy number as strong indicators of response to EGFR TKIs in lung cancer. [28][29][30] Rational combination strategies may overcome tumor resistance to EGFR-targeted therapies and expand their target treatment populations. The safety and efficacy of combinations of EGFR and IGF-1R inhibitors are currently being evaluated in several clinical studies (ClinicalTrials.gov: NCT00845039, NCT00617734, NCT00788957).…”

Activating K-Ras mutations outwith ‘hotspot’ codons in sporadic colorectal tumours – implications for personalised cancer medicine

“…Recent clinical data has shown a compelling association between K-Ras and B-Raf mutation status and response to EGFR blockade by cetuximab and panitumumab in the treatment of metastatic colorectal tumours (Benvenuti et al, 2007;Khambata-Ford et al, 2007;Freeman et al, 2008;Karapetis et al, 2008;Ramos et al, 2008). K-Ras mutations in colorectal tumours have been extensively documented, where recent meta analysis of more than 3000 tumours estimates an average K-Ras mutation frequency of 34.8% (Andreyev et al, 2001).…”

“…Recent clinical data convincingly associates response to anti-EGFR therapies with K-Ras mutation status in patients with metastatic colorectal cancer where, logically, response is preferentially observed in K-Ras wt tumours (Lievre et al, 2006;Benvenuti et al, 2007;Khambata-Ford et al, 2007;Freeman et al, 2008;Karapetis et al, 2008;Ramos et al, 2008;Loupakis et al, 2009;Van Cutsem et al, 2009) which retain the ability to respond to EGFR blockade. Our description of K-Ras gene amplification in a subset of wt tumours is of particular interest in this regard as increased K-Ras gene copy number may lead to a more active 'mutation'-like phenotype.…”

“…We and others have shown that K-Ras mutations are associated with significantly reduced survival in colorectal cancer patients (Andreyev et al, 2001;Conlin et al, 2005), although previous data is not entirely consistent (EtienneGrimaldi et al, 2008;Winder et al, 2009). K-Ras mutation status has recently been convincingly associated with response to the new generation EGFR antagonists cetuximab (Erbitux) and panitumumab (Vectibix), where response is preferentially observed in wt K-Ras tumours (Lievre et al, 2006;Benvenuti et al, 2007;Khambata-Ford et al, 2007;Freeman et al, 2008;Karapetis et al, 2008;Ramos et al, 2008;Loupakis et al, 2009;Van Cutsem et al, 2009). K-Ras mutation testing is therefore increasingly recommended to facilitate selection of the most appropriate patients for treatment with EGFR antagonists (McNeill, 2008;van Krieken and Tol, 2009).…”