Targeted therapies with monoclonal antibodies have been shown to improve the outcome of non-small cell lung cancer (NSCLC). Current strategies focus on the blockade of growth factor receptors and the inhibition of angiogenesis. Epidermal growth factor receptor (EGFR)-directed monoclonal antibodies in combination with platinum-based first-line chemotherapy have shown promising efficacy in phase II trials. In a phase III trial, cetuximab combined with cisplatin/ vinorelbine resulted in superior survival compared to chemotherapy alone in patients with advanced EGFR-positive NSCLC. Inhibition of angiogenesis has also been successfully applied as a new treatment strategy. Bevacizumab added to palliative chemotherapy has improved progression-free survival in two phase III trials and overall survival in one of these trials in selected patients with advanced non-squamous cell lung cancer. Bevacizumab is now approved for selected patients with advanced NSCLC in combination with platinum-based chemotherapy. Figitumumab is a monoclonal antibody against the insulin-like growth factor-1 receptor (IGF-1R) which demonstrated activity in preclinical models of NSCLC and in a phase II trial. Because of these promising results, three randomized, open-label, international phase III trials of figitumumab in patients with locally advanced or metastatic NSCLC are in progress. less...

First line combination chemotherapy (CT) using platinum-based doublets is established as a standard of care for advanced non-small cell lung cancer (NSCLC). Nevertheless, no significant advances have been recorded during the last years in this field. Therefore, there is a wide consensus among physicians that a plateau has already been reached with this strategy. Targeted therapy using tyrosine-kinase inhibitors (TKIs) and monoclonal antibodies emerged as a new field of development in the NSCLC therapeutics. Recently, the results of the phase III trials testing antibodies against vascular endothelial growth factor-VEGF (bevacizumab) and epidermal growth factor receptor-EGFR (cetuximab) challenged the paradigm of the platinum doublets as a gold standard in advanced NSCLC. Their appearance was enthusiastically commended both by patients and the oncological community. However, all medical oncologists have the responsibility to carefully analyze the real benefits of these new agents, to balance the advantages against the implicit risks of therapy and to make the decision having in mind the best interest of their patients. Last but not least, the associated health economic burden should also be considered. This paper addresses some issues related to the use of cetuximab and bevacizumab in advanced NSCLC. The main controversial aspects regarding patient selection, the real benefit of therapy, the molecular and clinical predictors, and the impact of other independent variables are carefully examined and presented. Due to many unsolved questions, no definite conclusions can be supported. The final decision about the optimal use of these agents is left to the clinical judgment of each treating physician. less...

BACKGROUND: Neoadjuvant chemoradiotherapy (CRT) reduces local tumor recurrence in locally advanced rectal cancer (LARC). This phase II study assessed neoadjuvant cetuximab with capecitabine-based CRT in LARC. METHODS: Patients with stage II/III LARC received capecitabine 1250 mg/m(2) twice daily for 2 weeks followed by intravenous cetuximab 400 mg/m(2) at week 3, then weekly intravenous 250 mg/m(2) cetuximab plus CRT including capecitabine 825 mg/m(2) twice daily (including weekends during radiotherapy) with radiotherapy of 45 Gy (25 x 1.8 Gy), 5 days a week for 5 weeks. Total mesorectal excision was scheduled 4-6 weeks following completion of CRT. The primary endpoint was pathological complete response (pCR). RESULTS: Thirty-seven patients were eligible for safety and efficacy. TMN staging at baseline was: T4N2, 11%; T3N2, 40%; T2N2, 3%; T3N1, 35%; T2N1, 3% and T3N0 8%. The most common adverse events included, grade 1/2 acneiform skin rash (86%), and grade 3 radiodermatitis, (16%), diarrhea (11%) and hypersensitivity (5%) pCR was achieved in 3 patients (8%). Overall-, T- and N-downstaging rates were 73%, 57% and 81% respectively. Total sphincter preservation rate was 76%, and 53% in 17 patients whose tumors were located within 5 cm from the anal verge. Non-fatal perioperative complications occurred in 13 patients (35%) with delayed wound healing occurring in 6 patients (16%). One death was recorded due to sepsis following colonic necrosis. CONCLUSION: Neoadjuvant cetuximab with capecitabine-based CRT is tolerable in patients with resectable LARC. Whilst the pCR rate was similar to recent reports, a high pathological downstaging rate was achieved. less...

A phase II clinical and molecular study of the Spanish group for digestive tumor therapy (TTD). PURPOSE: To evaluate the efficacy and safety of first-line single-agent cetuximab in fit elderly patients with metastatic colorectal cancer, as well as potential molecular predictive factors for efficacy. PATIENTS AND METHODS: Patients aged 70 or older with metastatic CRC without criteria for frailty and no prior treatment for advanced disease were treated with single-agent cetuximab 400mg/m(2) followed by weekly 250mg/m(2) until disease progression or unacceptable toxicity. RESULTS: Forty-one patients were included. Two patients achieved a complete response and 4 patients had a partial response for an overall response rate of 14.6%. Fifteen patients (36.6%) remained stable. Median time to progression was 2.9 months and median overall survival 11.1 months despite two-third of patients received chemotherapy at progression. Forty-five percent of EGFR gene copy number positive patients by FISH were progression-free at 12 weeks, in contrast with 12% of FISH negative patients (p=0.04). Grade 3 skin toxicity was reported in 5 patients (12.2%). Hypersensitivity infusion reactions were not reported and there were no toxic deaths CONCLUSION: Cetuximab is a safe monoclonal antibody with moderate activity in first-line metastatic colorectal cancer, but the present study does not support the use of cetuximab as single-agent in first-line fit elderly patients with metastatic CRC. less...

Insulin-like Growth Factor-1 (IGF-1) signaling system exerts a broad anti-apoptotic function and plays a crucial role in resistance to anti-cancer therapies. Exposure of MCF-7 breast cancer cells to IGF-1 rapidly and transiently induced tyrosine phosphorylation and activation of Phosphoinositide-Dependent Kinase-1 (PDK1). This was paralleled by Akt/Protein Kinase B and Protein Kinase C-zeta phosphorylation, at Thr308 and Thr410, respectively. IGF-1 treatment also enhanced PDK1 interaction with IGF-1 receptor (IGF-1R) in intact MCF-7 cells. Pull-down assays revealed that PDK1 bound IGF-1R in vitro, and the region encompassing amino acids 51-359 of PDK1 was necessary for the interaction. Synthetic peptides corresponding to IGF-1R C-terminus amino acids 1295-1337 (C43) and to PDK1 amino acids 114-141 reduced in vitro IGF-1R/PDK1 interaction in a concentration-dependent manner. Loading of fluoresceinated-C43 (FITC-C43) into MCF-7 cells significantly reduced IGF-1R/PDK1 interaction and phosphorylation of PDK1 substrates. Moreover, FITC-C43 intracellular loading reverted the protective effect of IGF-1 on growth factor deprivation-induced cell death. Finally, the inhibition of IGF-1R/PDK1 interaction and signalling by FITC-C43 was accompanied by 2-fold enhanced killing capacity of Cetuximab in human GEO colon adenocarcinoma cells and was sufficient to restore cell death in Cetuximab-resistant cell clones. Thus, disruption of PDK1 interaction with IGF-1R reduces IGF-1 survival effects in cancer cells and may enhance cell death by anti-cancer agents. less...

The strategies of incorporating monoclonal antibodies (MoABs) have now proved efficacy in the first-line treatment of advanced non-small cell lung cancer (NSCLC). These include targeting the vascular endothelial growth factor (VEGF) or epidermal growth factor receptor (EGFR). Bevacizumab is a MoAB targeting the vascular endothelial growth factor (VEGF), an important mediator of new blood vessel formation. Cetuximab is a MoAB directed at EGFR. Binding cetuximab to EGFR blocks signal transduction and promotes receptor internalization and degradation. In this review, we present current data of bevacizumab and cetuximab for the first line treatment of advanced NSCLC. We also refer to their potential for Asian patients with advanced NSCLC in the first-line setting. less...

Cetuximab is a monoclonal antibody targeting epidermal growth factor receptor (EGFR). The present study investigated the association between germline genetic polymorphisms and the treatment outcome of cetuximab plus modified leucovovin, fluorouracil, and oxaliplatin (FOLFOX)6 chemotherapy in advanced gastric cancer (AGC). DNA from peripheral blood mononuclear cells of 38 patients enrolled in a phase II study of cetuximab plus modified FOLFOX6 were analyzed for 16 polymorphisms in eight genes (EGFR, epidermal growth factor, transforming growth factor-alpha (TGFA), thymidylate synthase, excision repair cross-complementation group 1, Xeroderma pigmentosum group D, and fragment c gamma receptors (FCGR)2A and 3A). The EGFR intron 1 CA repeat polymorphism was associated with survival. Twenty-one patients had low repeats (sum of both alleles </=37), and 17 patients had high repeats (sum >/=38). Patients with low CA repeats had longer progression-free survival (adjusted hazard ratio [HR] 0.42 [95% confidence interval [CI] 0.19-0.96], P = 0.040) and overall survival (adjusted HR 0.40 [95% CI 0.16-0.99], P = 0.048) compared with patients with high CA repeats. In addition, the tumor EGFR expression was higher in patients with a lower number of CA repeats. The association between the CA repeat status and survival was not found in a separate cohort of AGC patients (n = 68) treated only with modified FOLFOX6. These results suggest that the EGFR intron 1 CA repeat polymorphism could be a useful, predictive biomarker of cetuximab efficacy in AGC and merits further investigation in randomized studies. (Cancer Sci 2009). less...

Since late 1990s, many molecular target agents have been introduced to clinical trials for various kinds of tumors, and some of them showing significant benefits have been approved. However, these global trials were mainly conducted outside Japan, and the 'drag lag' has been a serious problem in Japan recently. Nowadays, Japanese institutions have been participating in some global trials, and the drug lags are getting shorter. For colorectal cancer, molecular target agents such as bevacizumab and cetuximab have been approved in Japan, resulting in improved clinical outcomes. For gastric cancer, Japanese institutions not only contribute to the global Phase III trials of trastuzumab and bevacizumab but also show leadership in the early development of other new agents. For pancreatic cancer, only erlotinib has shown a survival benefit in these 10 years. Worldwide approach including Japan is warranted to achieve better clinical outcomes. For liver cancer, although Japanese institutions did not participate even in the Asian trial of sorafenib, it has been approved in Japan. For esophageal cancer, because there has been no new molecular target agents developed by pharmaceutical companies, investigator-initiated registration trial will play an important role. For all gastrointestinal malignancies, molecular target agents have made a progress in their treatments. In the near future, Japanese institutions will participate in more and more global trials and should play a specific role in worldwide drug development. Furthermore, the optimal use of these new drugs, molecular target agents, based on the daily practice should also be explored in Japan. less...

KRAS mutations are a strong predictive marker of resistance to anti-EGFR antibodies in advanced colorectal cancer (CCR) but only a subset of wild-type (WT) KRAS patients are responders, suggesting the existence of additional markers of resistance to this treatment. The activation of EGFR downstream signaling pathways may be one of these ones.In a series of 42 patients with advanced CRC treated with cetuximab/panitumumab, for whom KRAS status was previously determined, we retrospectively analyzed the intratumor expression of EGFR downstream signaling phosphoproteins of the RAS/MAPK and PI3K/AKT pathways (pERK1/2, pMEK1, pAKT, pP70S6K and pGSK3beta) using Bio-Plex(R) phosphoprotein array. Association with tumor response, progression-free survival (PFS) and overall survival (OS) was assessed.The expression of all the phosphoproteins was higher in KRAS mutated tumors than in WT tumors. The expression of pP70S6K was lower in responders than in non-responder patients. In univariate analysis, patients with high pMEK1 or pP70S6K expression had a shorter PFS than those with low expression. Patients with high pP70S6K expression also had a shorter OS. In multivariate analysis, PFS was shorter for patients with high pMEK1 or pP70S6K expression, independently of KRAS status, as OS for patients with high pP70S6K expression. Therefore, WT KRAS patients with high pP70S6K expression had a shorter survival than those with low expression.Our results suggest the importance of EGFR downstream signaling phosphoproteins expression in addition to KRAS status to define the subgroup of patients who will not benefit from anti-EGFR therapy. (c) 2010 UICC. less...

Members of the epidermal growth factor receptor (EGFR) family and their associated ligands are commonly expressed by synovial cells, and may be involved in the synovial hyperplasia seen in rheumatoid arthritis and its disease progression. This family of receptors is also expressed in cancer cells, and EGFR targeted therapy is now a mainstay of anticancer therapy. Cetuximab (Erbitux) is a monoclonal antibody directed against the EGFR extracellular receptor that has received Food and Drug Administration approval for the treatment of colorectal cancer as well as head and neck cancer. We report a case of a 61-year-old woman with an extensive history of rheumatoid arthritis requiring multiple therapies, who experienced a surprising remission of her disease and its symptoms while being treated with cetuximab for her head and neck cancer. The case as well as possible mechanisms of action are discussed. Further clinical investigations are clearly warranted. less...