Efficacy Of Cetuximab In Patients Research Articles

Germline Polymorphisms in Genes Involved in the Antioxidant System Predict the Efficacy of Cetuximab in Metastatic Colorectal Cancer Patients Enrolled in FIRE-3 Trial

BackgroundReactive oxygen species activate EGFR/RAS/MAPK signaling either through the inactivation of phosphatases or by direct oxidation of kinases. We hypothesized that functional single-nucleotide polymorphisms (SNPs) in antioxidant genes link to the efficacy of cetuximab in patients with metastatic colorectal cancer (mCRC). Patients and MethodsWe analyzed genomic and clinical data from FIRE-3, a phase III trial comparing cetuximab and bevacizumab along with FOLFIRI in untreated mCRC patients. Genomic DNA extracted from blood samples was genotyped. Thirteen functional SNPs in antioxidant genes were tested for associations with clinical outcomes. ResultsIn total, 236 patients were included (FOLFIRI/cetuximab arm, n = 129; FOLFIRI/bevacizumab arm, n = 107). In univariate analysis, two SNPs (TXN2 rs4821494 and GPX4 rs4807542) were significantly associated with overall survival (OS) in the FOLFIRI/cetuximab arm. Multivariate analysis confirmed the significant association of TXN2 rs4821494 (T/T vs. any G allele, hazard ratio = 2.47, 95% confidence interval = 1.06–5.72, P = .03). In the FOLFIRI/bevacizumab arm, no SNPs were significantly associated with clinical outcomes. Treatment-by-SNP interaction test confirmed the predictive value of TXN2 rs4821494 (OS: P = .03). ConclusionTXN2 rs4821494 involved in the antioxidant system may predict the efficacy of cetuximab-based first-line chemotherapy in mCRC, warranting further validation studies.

Upregulation of secreted phosphoprotein 1 affects malignant progression, prognosis, and resistance to cetuximab via the KRAS/MEK pathway in head and neck cancer.

Acquired resistance is a barrier to cetuximab efficacy in patients with head and neck squamous cell carcinoma (HNSCC). Secreted phosphoprotein 1 (SPP1) is involved in various biological processes, including immune responses, cancer progression, and prognosis in many cancers, while little is known in HNSCC. Bioinformatics methods were used to identify candidate genes and further in vivo and in vitro experiments were performed to examine and validate the function of SPP1. We found that SPP1 was upregulated and has been found to have an oncogenic role in HNSCC. We further confirmed that overexpression of SPP1 affected proliferation, migration, invasion, and survival, and inhibited apoptosis, whereas silencing of SPP1 yielded opposite results to those of SPP1 overexpression. In addition, activation of the KRAS/MEK pathway contributed to the SPP1-induced malignant progression of HNSCC and resistance to cetuximab. Furthermore, SPP1 knockdown or an MEK inhibitor overcame this cetuximab-resistance pattern. Taken together, our findings for the first time identify the role of SPP1 in tumor promotion, prognostic prediction, and potential therapeutic targeting, as well as resistance to cetuximab in HNSCC.

Primary tumor location predicts poor clinical outcome with cetuximab in RAS wild-type metastatic colorectal cancer

BackgroundIn metastatic colorectal cancer, the location of the primary tumor has been suggested to have biological significance. In this study, we investigated whether primary tumor location affects cetuximab efficacy in patients with RAS wild-type metastatic colorectal cancer.MethodsGenotyping by the SequenomMassARRAY technology platform (OncoMap) targeting KRAS, NRAS, PIK3CA, and BRAF was performed in tumors from 307 patients who had been given cetuximab as salvage treatment. Tumors with mutated RAS (KRAS or NRAS; n = 127) and those with multiple primary location (n = 10) were excluded. Right colon cancer was defined as a tumor located in the proximal part to splenic flexure.ResultsA total of 170 patients were included in the study (right versus left, 23 and 147, respectively). Patients with right colon cancer showed more mutated BRAF (39.1% vs. 5.4%), mutated PIK3CA (13% vs. 1.4%), poorly differentiated tumor (17.4% vs. 3.4%), and peritoneal involvement (26.1% vs. 8.8%) than those with left colon and rectal cancer. Right colon cancer showed poorer progression-free survival (2.0 vs.5.0 months, P = 0.002) and overall survival (4.1 months and 13.0 months, P < 0.001) than the left colon and rectal cancer. By multivariable analysis, BRAF mutation, right colon primary, poorly differentiated histology, and peritoneal involvement were associated with risk of death.ConclusionsIn RAS wild-type colon cancer treated with cetuximab as salvage treatment, right colon primary was associated with poorer survival outcomes than left colon and rectal cancer.

Association between miR-31-3p expression and cetuximab efficacy in patients with KRAS wild-type metastatic colorectal cancer: a post-hoc analysis of the New EPOC trial.

BackgroundHigh miR-31-3p expression is associated with inferior outcomes in KRAS wild-type (WT) advanced colorectal cancer patients treated with anti-EGFR therapy. This study evaluated miR-31-3p expression in patients with operable colorectal liver metastases (LM) enrolled in the New EPOC study.MethodsMiR-31-3p expression was measured in primary tumors (PT) from 149 KRAS WT patients including 71 receiving chemotherapy alone (CT) and 78 receiving chemotherapy plus cetuximab (CTX). Each treatment arm was split into tertiles based on miR-31-3p expression levels. MiR-31-3p expression was also measured in LM from 94 patients with tumor tissue available.ResultsThe median progression-free survival for the combined populations with mid or high miR-31-3p expression was shorter in the CTX versus the CT arm (26.7 months versus 12.3 months, HR=2.28 95%CI 1.27; 4.09 p=0.006). Low miR-31-3p expressers had similar outcomes irrespective of treatment (HR=1.06 95%CI 0.43; 2.61 p=0.9). MiR-31-3p expression was correlated between paired PT and LM samples in the CT group but not in the CTX group.ConclusionsPatients with low miR-31-3p expression in the New EPOC study were not harmed by the addition of cetuximab. This supports miR-31-3p as a promising predictive biomarker for anti-EGFR therapy in KRAS WT advanced colorectal cancer.

The impact of primary tumor location on efficacy of cetuximab in metastatic colorectal cancer patients with different Kras status: a systematic review and meta-analysis.

ObjectiveTo assess the prognostic role of primary tumor location along with Kras status in metastatic colorectal cancer (mCRCs) treated with cetuximab.Materials and MethodsDatabases of EMBASE, Pubmed, the Cochrane library, China National Knowledge Infrastructure and other databases from inception to July 2016 were searched. Randomized controlled trial (RCT) and/or retrospective studies of influence of primary tumor location on efficacy of cetuximab in patients with mCRC were identified. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival (OS), overall response rate (ORR) and disease control rate (DCR).ResultsTen studies including 2977 cases were finally included. The results of meta-analysis were in favor of cetuximab to patients with left-sided colorectal cancer in terms of OS (HR = 0.52, 95% CI: 0.40–0.66; p < 0.01), PFS (HR = 0.64, 95% CI: 0.58–0.70; p < 0.01), and ORR (OR = 2.17, 95% CI: 1.57–2.99; p < 0.01). Patients with right-sided CRC gained less benefit from cetuximab in terms of OS (HR = 1.89, 95% CI: 1.43–2.50; p < 0.01), compared with left-sided CRC. Regarding Kras status, left-sided mCRC with wild type Kras had better PFS (HR = 0.61, 95% CI: 0.51–0.74; p < 0.01) and OS (HR = 0.49, 95% CI: 0.35–0.69; p < 0.01) than right-sided cases when treated with cetuximab. We also found that cetuximab was both significantly effective in different treatment lines and regions when comparing by primary tumor locations (p < 0.01).ConclusionsmCRC Patients with left-sided, wild type Kras have a better prognosis than those with right-sided diseases when treated with cetuximab. The clinical application of cetuximab should be determined by the primary tumor location and molecular gene mutation status.

HER2 Amplification and Cetuximab Efficacy in Patients With Metastatic Colorectal Cancer Harboring Wild-type RAS and BRAF

BackgroundCetuximab has shown clinical benefit in patients with metastatic colorectal cancer (mCRC) harboring wild-type RAS. Human epidermal growth factor receptor 2 (HER2) amplification may be a mechanism of cetuximab resistance. We evaluated the association between HER2 amplification and cetuximab efficacy in patients with mCRC harboring wild-type RAS and BRAF. Patients and MethodsBetween December 2003 and June 2013, we identified 142 patients with mCRC whose tumors harbored both wild-type exons 2, 3, and 4 in KRAS and NRAS, and wild-type exon 15 in BRAF using high throughput sequencing (OncoMap version 4.0). All patients received cetuximab after oxaliplatin, irinotecan, and fluoropyrimidine failure. HER2 status was determined using immunohistochemistry and silver in situ hybridization (SISH) and correlated with cetuximab efficacy. ResultsOf 142 RAS and BRAF wild-type tumors, we observed 7 cases (4.9%) of HER2 amplification by SISH. After a median follow-up of 13.2 months (range, 1.4-78.1 months), median progression-free survival (PFS) was significantly different according to HER2 status: 3.1 months in patients with HER2 amplification compared with 5.6 months in those with non-amplified HER2 (hazard ratio, 2.73; 95% confidence interval, 1.18-6.31; P = .019). Overall survival (OS) was not significantly different between groups, although there was a tendency towards shorter OS in patients with HER2-amplified tumors (hazard ratio, 1.31; 95% confidence interval, 0.61-2.82; 10.1 vs. 13.5 months; P = .488). ConclusionsHER2 amplification is predictive of shorter PFS after cetuximab treatment in patients with mCRC harboring wild-type RAS and BRAF. Further study is warranted for this patient population.

521P - Association between HER2 amplification and cetuximab efficacy in patients with RAS wild-type metastatic colorectal cancer

Cetuximab has shown clinical benefit in patients with metastatic colorectal cancer (mCRC) harbouring wild-type RAS. HER2 amplification has been suggested as one of the resistant mechanisms of cetuximab treatment. We evaluated association between HER2 amplification and cetuximab efficacy in mCRC patients harbouring extended RAS wild-type. Between December 2003 and June 2013, we found 253 mCRC patients whose tumor harboured wild type in exon 2/3/4 both of KRAS and NRAS by high throughput sequencing (OncoMap version 4.0) and were treated with cetuximab as 2nd or later-line. We finally included 243 mCRC cases whose HER2 status could be determined by both immunohistochemical (IHC) scoring according to HERACLES criteria and silver in-situ hybridisation (SISH). Progression-free survival (PFS) and overall survival (OS) were analysed in homogenous group (n = 149) who were progressed after oxaliplatin, irinotecan and fluoropyrimidines. The median age was 55 years (range 19–76 years); 168 patients (69.1%) were male. Of the 243 RAS wild-type tumor, we observed 11 cases (4.5%) of HER2 amplification (table). After the median follow-up of 13.5 months (range, 0.4–78.1), median PFS was statistically different according to the HER2 status: 3.1 months in patients harbouring HER2 amplification vs 5.7 months in those harbouring non-amplified HER2 (p = 0.013). OS was not statistically different according to the HER2 status although there was a tendency towards shorter OS in patients harbouring HER2 amplification (10.1 vs 13.5 months, p = 0.408).Tabled 1HER2 IHC (HERACLES criteria)SISHNegativeEquivocalPositiveTotalAmplification1†HER2/CEP17 ratio 3.31HER2/CEP17 ratio 2.79†HER2/CEP17 ratio >5 (all cases)11No amplification22930232Total23049243† HER2/CEP17 ratio 3.3†† HER2/CEP17 ratio 2.7††† HER2/CEP17 ratio >5 (all cases) Open table in a new tab HER2 amplification is associated with shorter PFS after cetuximab in mCRC patients harbouring extended RAS wild-type. Recent study of dual targeting of EGFR and HER2 demonstrated promising result; further study is warranted for this population.

Association of right-sided colon cancer with poor efficacy of cetuximab in patients with RAS wild-type metastatic colorectal cancer.

3601Background: Right-sided colon cancer (RC) is distinct from left-sided colorectal cancer (LC) in terms of embryology, pathology and genetics. Previous reports have shown that RC have more KRAS a...

Use of a High-Throughput Genotyping Platform (OncoMap) for RAS Mutational Analysis to Predict Cetuximab Efficacy in Patients with Metastatic Colorectal Cancer.

PurposeCetuximab demonstrates improved efficacy outcomes in patients with metastatic colorectal cancer (mCRC) harboring wild-type KRAS exon 2. Resistance to cetuximab is mediated by activating less frequent mutations in the RAS genes beyond KRAS exon 2. We performed extended RAS Mutational analysis using a high-throughput genotyping platform (OncoMap) and evaluated extended RAS analysis for predicting cetuximab efficacy in patients harboring wild-type KRAS exon 2 tumors following Sanger sequencing.Materials and MethodsExtended RAS analysis was performed on 227 wild-type KRAS exon 2 mCRC patients who received cetuximab as salvage treatment using OncoMap ver. 4.0. Targeted genes included exon 2, exon 3, and exon 4, both in KRAS and NRAS, and included BRAF exon 15. We assessed efficacy by the new RAS mutation status.ResultsThe OncoMap detected 57 additional mutations (25.1%): 25 (11%) in KRAS exon 2 and 32 (14.1%) beyond KRAS exon 2. Survival differences were observed after dividing patients into the wild-type RAS group (n=170) and mutant RAS group (n=57) using OncoMap. Progression-free survival was 4.8 months versus 1.8 months (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.32 to 0.61), and overall survival was 11.9 months versus 8.4 months (HR, 0.65; 95% CI, 0.47 to 0.88).ConclusionSanger sequencing is not sufficient for selecting candidates for cetuximab treatment. High-throughput extended RAS genotyping is a feasible approach for this purpose and identifies patients who might benefit from cetuximab treatment.

156P High-throughput genotyping platform (OncoMap), a precise tool for predicting cetuximab efficacy in patients with metastatic colorectal cancer

156P High-throughput genotyping platform (OncoMap), a precise tool for predicting cetuximab efficacy in patients with metastatic colorectal cancer

Polymorphisms in Genes Involved in EGFR Turnover Are Predictive for Cetuximab Efficacy in Colorectal Cancer.

Transmembrane receptors, such as the EGFR, are regulated by their turnover, which is dependent on the ubiquitin-proteasome system. We tested in two independent study cohorts whether SNPs in genes involved in EGFR turnover predict clinical outcome in cetuximab-treated metastatic colorectal cancer (mCRC) patients. The following SNPs involved in EGFR degradation were analyzed in a screening cohort of 108 patients treated with cetuximab in the chemorefractory setting: c-CBL (rs7105971; rs4938637; rs4938638; rs251837), EPS15 (rs17567; rs7308; rs1065754), NAE1 (rs363169; rs363170; rs363172), SH3KBP1 (rs7051590; rs5955820; rs1017874; rs11795873), SGIP1 (rs604737; rs6570808; rs7526812), UBE2M (rs895364; rs895374), and UBE2L3 (rs5754216). SNPs showing an association with response or survival were analyzed in BRAF and RAS wild-type samples from the FIRE-3 study. One hundred and fifty-three FOLFIRI plus cetuximab-treated patients served as validation set, and 168 patients of the FOLFIRI plus bevacizumab arm served as controls. EGFR FISH was done in 138 samples to test whether significant SNPs were associated with EGFR expression. UBE2M rs895374 was significantly associated with progression-free survival (log-rank P = 0.005; HR, 0.60) within cetuximab-treated patients. No association with bevacizumab-treated patients (n = 168) could be established (P = 0.56; HR, 0.90). rs895374 genotype did not affect EGFR FISH measurements. EGFR recycling is an interesting mechanism of secondary resistance to cetuximab in mCRC. This is the first report suggesting that germline polymorphisms in the degradation process predict efficacy of cetuximab in patients with mCRC. Genes involved in EGFR turnover may be new targets in the treatment of mCRC.

FOLFIRI and Cetuximab Every Second Week for First-Line Treatment of KRAS Wild-Type Metastatic Colorectal Cancer According to Phosphatase and Tensin Homolog Expression: A Phase II Study

BackgroundRetrospective studies have suggested that phosphatase and tensin homolog (PTEN) expression might predict the efficacy of cetuximab in patients with KRAS wild-type metastatic colorectal cancer (mCRC). The present study was designed to prospectively evaluate the efficacy of first-line irinotecan, fluorouracil, and folinate (FOLFIRI) plus cetuximab every second week according to PTEN expression. Patients and MethodsOriginally, patients with KRAS wild-type mCRC were randomly assigned to receive either FOLFIRI or cetuximab plus FOLFIRI (FOLFIRI-C). After a protocol amendment, the FOLFIRI arm was discontinued, and additional patients received FOLFIRI-C. Cox proportional hazard models were used to investigate the effect of PTEN and MET expression and BRAF and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit α mutations on progression-free survival (PFS) and overall survival (OS). ResultsA total of 35 and 54 patients received FOLFIRI and FOLFIRI-C, respectively. For the patients assigned to FOLFIRI and FOLFIRI-C, the median OS was 17.7 and 23.3 months and the median PFS was 8.2 and 6.6 months, respectively. For patients receiving FOLFIRI-C, the loss of PTEN expression did not affect PFS or OS. Significant interactions for PFS were detected between the MET expression levels (P = .047) and BRAF mutation (P = .018) and treatment. On univariate analysis, BRAF mutation was significantly associated with shorter OS for patients receiving either FOLFIRI-C (P = .016) or FOLFIRI (P = .035). Multivariate analysis confirmed the independent prognostic value of BRAF mutation on OS and that of MET expression levels on PFS (P = .025) and OS (P = .028) but only in the patients receiving FOLFIRI alone. Adverse events with FOLFIRI-C were consistent with those expected from FOLFIRI plus weekly cetuximab. ConclusionAlthough prospective analysis of PTEN did not allow a validation of the prognostic value of this biomarker, an every second week cetuximab schedule, in addition to first-line FOLFIRI, was effective and well tolerated. The possible predictive value of MET expression levels warrants additional investigation.

Predicting cetuximab efficacy in patients with advanced colorectal cancer

Predicting cetuximab efficacy in patients with advanced colorectal cancer Ibrahim H Sahin, Christopher R Garrett Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA Abstract: Cetuximab has demonstrated activity, both as monotherapy, and in combination with cytotoxic chemotherapy, albeit modest. Efforts over the last decade have focused on determining which patient populations are most likely to benefit from this chimeric monoclonal antibody therapy. As the antibody targets the epidermal growth factor receptor (EGFR), cell surface expression by immunohistochemistry was hypothesized to be a biomarker of clinical efficacy; subsequent clinical trials have shown that this was not the case. Tumor KRAS mutation (the most frequently observed site is at codon 12) has been shown to be a negative biomarker (ie, a marker of cetuximab resistance); since 2008, treatment of patients with cetuximab has been restricted to those whose tumors do not harbor a KRAS mutation. There is considerable heterogeneity of KRAS mutations, and studies are ongoing to determine whether cetuximab resistance extends to those patients whose tumors have a KRAS codon 13, 61, and 164, mutation. EGFR gene copy, or more precisely a lack of increase in EGFR gene copy number, has been demonstrated to be a negative biomarker of EGFR efficacy; currently, it is not in routine use as a clinical standard of care. Tumor BRAF status, NRAS status, and PIK3CA mutation status are being evaluated as additional potential negative biomarkers of treatment efficacy. High expression of the receptor ligands epiregulin and amphiregulin has been shown to be a positive biomarker for treatment efficacy and is continuing to be studied clinically. After almost 10 years following the widespread introduction of cetuximab into the clinic as a treatment for metastatic colorectal cancer, the story of identifying suitable biomarkers of efficacy is still evolving. The tremendous tumor heterogeneity at the molecular level and the cell complexity of signaling pathways suggest that there is still a significant amount of work to be done to optimally define those patients most likely to benefit from this form of therapy. Keywords: biomarkers, epidermal growth factor receptor, EGFR, KRAS mutation

Genes involved in EGFR-degradation to predict for efficacy in metastatic colorectal cancer patients treated with cetuximab.

3557 Background: As many transmembrane receptors, the epithelial growth factor receptor (EGFR) has a highly regulated turnover leading to inactivation and recycling or degradation after activation. This process can be divided into four different phases: receptor endocytosis, ubiquitation/neddylation, recycling and degradation. We tested whether functional significant single nucleotide polymorphisms in genes involved in the degradation pathway will predict clinical outcome (response, PFS and OS) in 108 patients with metastatic colorectal cancer enrolled in clinical trials and treated with cetuximab. Methods: Genomic DNA was isolated from blood from 108 patients treated with cetuximab enrolled in one of two clinical trials. All patients were KRAS and BRAF wildtyp. 20 SNPs were selected based on the involvement in receptor endocytosis (CBL, CIN85, endophilin) ubiquitation/neddylation, recycling and degradation (CBL, EPS15, Ubc12, UbcH7). Minor allele frequency had to by higher than 10%. PCR and product sequencing were done using standard procedures. Uni- and multivariate analyses, adjusting for age, gender, rash and racial background, were carried out. Results: In univariate analysis, rs895374 (HR: 1.69; p= 0.03), which is located in the exome of UbcH7, was able to separate patient cohorts significantly in perspective of progression free survival (CC = 5.7mo, CA= 3.6mo, AA= 3.4mo). Using multivariate analysis, rs895375 stayed to be a significant predictor of progression free survival with a Hazard ratio of 2.08 (95% CI 1.24 – 3.48) and a p value of 0.005. UbcH7 plays a pivotal role in the process of neddylation (adding NEDD8 to the EGFR), which switch the balance between recycling and degradation of the EGFR towards degradation. Conclusions: The process of EGFR recycling is important mechanism of resistance of cetuximab in colorectal cancer. This is the first report suggesting that germline polymorphisms in the degradation process may predict efficacy of cetuximab in patients with metastatic colorectal cancer. Anti-EGFR antibody like Sym004 might overcome this resistance mechanism by preventing EGFR recycling.

Pretreatment characteristics and early indicators of long-term efficacy of cetuximab in patients with recurrent/metastatic squamous cell carcinoma of the head and neck (rmSCCHN).

e17015 Background: Cetuximab has established activity in rmSCCHN as a single agent as well as in conjunction with chemotherapy. Combination treatment protocols lead to significant toxicity. It would be of interest to identify pretreatment characteristics and early indicators of long-term cetuximab efficac. Methods: rmSCCHN patients were analysed, who participated in trials of chemotherapy plus cetuximab, followed by cetuximab maintenance. Patients were stratified into two groups of long term exposure (LTE) and short term exposure (STE) of cetuximab using 6 months as cut-off. Factors considered for analysis included age, sex, performance status, smoking behavior, primary tumor site, time from primary to treatment for rm-disease, number of chemotherapy cycles received, response, toxicity, and reason for treatment discontinuation. Results: In 2 institutions, 61 patients were enrolled in 5 clinical trials between 2008 and 2011. Cetuximab was administered in standard dose and schedule until disease progression or unacceptable toxicity. 27 patients received cetuximab &lt;6 mo (STE, median 1.5 mo) and 34 &gt;6 mo (LTE, median 9 mo). Patients with LTE as compared to STE only differed in 2 characteristics: oral/oropharyngeal primary (56% vs. 41%) and median chemotherapy cycles received (6 vs. 2). Comparing LTE to STE, treatment discontinuation during the chemotherapy phase was due to toxicity in 14 vs. 37% or death in 4 vs. 15%. Median OS in LTE vs. STE was 18 vs. 4 mo. Conclusions: LTE was associated with a huge improvement of OS. Toxicity of chemotherapy was a relevant factor for early discontinuation of combination treatments, limiting the overall efficacy of cetuximab. Results may be improved by further intensification of the already implemented proactive toxicity management, but also by development of less toxic chemotherapy schedules.

Cetuximab efficacy in patients treated routinely in university hospitals

The aim of this study was to evaluate the efficacy and tolerance of cetuximab (Cx) in patients with irinotecan-refractory metastatic colorectal cancer (IRMCRC) treated routinely at five university hospitals. Data from all patients treated with Cx (N=105) during the study period (between January 2004 and September 2005) were included in the analysis. Median number of Cx infusions was 12 (range: 1 to 62). Objective response rate was 24.8%; stable disease in 23.8%; progression in 34.3%; 17.1% of the patients were not evaluable. Digestive and hematological adverse events were grade III in 20% and 12%, respectively, and grade IV in 12% and 11%, respectively. Response rates were higher in patients with acne-like rashes than in patients without (P=0.005). Median time to tumor progression (TTP; intention-to-treat) was 3.9 months (95% CI: 2.6-4.8). Median overall survival after Cx initiation was 8.3 months (95% CI: 6.310.7). Four prognostic factors were significantly associated with a shorter TTP: center (Center 4: HR=2.25, 95% CI: 1.16-4.35, P=0.017); absence of hepatic metastases (HR=2.5, 95% CI: 1.434.37, P=0.001); WHO performance status (HR=1.47, 95% CI: 1.10-1.96, P=0.008); and number of metastatic sites (HR=1.30, 95% CI: 1.05-1.60, P=0.014). This analysis of a random population of IRMCRC patients supports Cx efficacy and feasibility, and is in agreement with the results of the BOND study.

Phase II Trial of Cetuximab in Patients With Previously Treated Non–Small-Cell Lung Cancer

To determine the efficacy of cetuximab in patients with recurrent or progressive non-small-cell lung cancer (NSCLC) after receiving at least one prior chemotherapy regimen. This was an open-label, phase II study of patients with epidermal growth factor receptor (EGFR) -positive and EGFR-negative advanced NSCLC with Eastern Cooperative Oncology Group performance status 0 to 1. Patients received cetuximab 400 mg/m2 intravenously (IV) during 120 minutes on week 1 followed by weekly doses of cetuximab 250 mg/m2 IV during 60 minutes. A cycle was considered as 4 weeks of treatment and therapy was continued until disease progression or intolerable toxicities. The primary end point was to assess response rate. Secondary end points included an estimation of time to progression and survival. Patient and disease characteristics (n = 66) included EGFR-positive status (n = 60); EGFR-negative status (n = 6); number of prior regimens (one, n = 28; two, n = 27; > or = three, n = 11); male (n = 41); female (n = 25); adenocarcinoma (n = 36); and smoking status (never, n = 13; former, n = 45; current, n = 8). Grade 3/4 toxicities included acne-like rash (6.1%), anaphylactic reactions (1.5%), and diarrhea (1.5%). The response rate for all patients (n = 66) was 4.5% (95% CI, 0.9% to 12.7%) and the stable disease rate was 30.3% (95% CI, 19.6% to 42.9%). The response rate for patients with EGFR-positive tumors (n = 60) was 5% (95% CI, 1.0% to 13.9%). The median time to progression for all patients was 2.3 months (95% CI, 2.1 to 2.6 months) and median survival time was 8.9 months (95% CI, 6.2 to 12.6 months). Although the response rate with single-agent cetuximab in this heavily pretreated patient population with advanced NSCLC was only 4.5%, the disease control rates and overall survival seem comparable to that of pemetrexed, docetaxel, and erlotinib in similar groups of patients.