Zenta Tsuchihashi

Multicenter Phase II and Translational Study of Cetuximab in Metastatic Colorectal Carcinoma Refractory to Irinotecan, Oxaliplatin, and Fluoropyrimidines

PURPOSEnThis multicenter study evaluated the antitumor activity of cetuximab, an immunoglobulin G1 antibody directed at the epidermal growth factor receptor (EGFR), in metastatic colorectal carcinoma (CRC) refractory to irinotecan, oxaliplatin, and a fluoropyrimidine. It also evaluated the safety, pharmacokinetics, immunokinetics, and biologic determinants of activity.nnnPATIENTS AND METHODSnPatients with metastatic CRC, whose tumors demonstrated EGFR immunostaining and were refractory to irinotecan, oxaliplatin, and fluoropyrimidines, were treated with cetuximab at a loading dose of 400 mg/m2 followed by 250 mg/m2 weekly. An independent review committee (IRC) reviewed responses. Blood was collected for cetuximab pharmacokinetics and to detect antibodies to cetuximab. EGFR gene sequencing of the tyrosine kinase domain and gene copy number assessments were performed.nnnRESULTSnThe response rates in 346 patients, as determined by the investigators and IRC, were 12.4% (95% CI, 9.1 to 16.4) and 11.6% (95% CI, 8.4 to 16.4). The median progression-free survival (PFS) and survival times were 1.4 months (95% CI, 1.4 to 2.1) and 6.6 months (95% CI, 5.6 to 7.6), respectively. An acneiform rash occurred in 82.9% of patients; grade 3 rash was observed in 4.9%. Response and survival related strongly to the severity of the rash. In contrast, clinical benefit did not relate to EGFR immunostaining. EGFR tyrosine kinase domain mutations were not identified, and EGFR gene copy number did not relate to response or PFS, but to survival (P = .03).nnnCONCLUSIONnCetuximab is active and well tolerated in metastatic CRC refractory to irinotecan, oxaliplatin, and fluoropyrimidines. The severity of rash was related to efficacy. Neither EGFR kinase domain mutations nor EGFR gene amplification appear to be essential for response to cetuximab in this setting.

Responsiveness to Cetuximab without Mutations in EGFR

To the Editor: A large amount of information suggests that mutations in the kinase domain of epidermal growth factor receptor (EGFR) are critical for the efficacy of EGFR kinase inhibitors.1–3 However, the effect of EGFR mutations on the response to cetuximab has not been directly investigated. Barber et al.4 reported the absence of EGFR mutations in colorectal cancers and speculated that EGFR mutations were not required for the response to cetuximab, since it was an efficacious agent against this type of tumor.5 We sequenced the kinase domain of EGFR (exons 18, 19, and 21) in tumor samples from 38 .xa0.xa0.

Evaluation of the Paraoxonases as Candidate Genes for Stroke. Gln192Arg Polymorphism in the Paraoxonase 1 Gene Is Associated With Increased Risk of Stroke

Background and Purpose— The paraoxonases are involved in protecting low-density lipoprotein (LDL) from lipid oxidation. Paraoxonase 1 (PON1) was implicated in susceptibility to coronary artery disease and stroke in previous studies. We evaluated, in a comprehensive way, all 3 paraoxonase genes for association with stroke observed in the Cholesterol and Recurrent Events (CARE) trial. Methods— Over 2500 subjects enrolled in the CARE trial were genotyped for 14 single nucleotide polymorphisms, including 7 newly identified in this study, in the 3 paraoxonase genes. Results— A glutamine (Gln)/arginine (Arg) polymorphism at amino acid residue 192 in PON1 was significantly associated with stroke (P=0.003 in multivariate analysis, including age, sex, LDL, hypertension, diabetes, smoking, and pravastatin treatment as covariates). The odds ratios were 2.28 (95% CI, 1.38 to 3.79) for Gln/Arg heterozygotes and 2.47 (95% CI, 1.18 to 5.19) for Arg/Arg homozygotes compared with Gln/Gln homozygotes. These results are consistent with 2 of 3 other published studies. In combined analysis of all 4 studies, the association between Gln192Arg SNP and stroke was highly significant (&khgr;28df=45.58, P<0.000001). Sequence analysis of the PON1 gene from seventy stroke cases revealed a novel nonsense mutation at codon 32 in one stroke case, which was not detected in over 2500 unaffected individuals. Polymorphisms in the PON2 and PON3 genes were not associated with stroke. Conclusions— These results suggest that Gln192Arg genotype is an important risk factor for stroke.

Gene expression profiling of whole blood in ipilimumab-treated patients for identification of potential biomarkers of immune-related gastrointestinal adverse events.

BackgroundTreatment with ipilimumab, a fully human anti-CTLA-4 antibody approved for the treatment of advanced melanoma, is associated with some immune-related adverse events (irAEs) such as colitis (gastrointestinal irAE, or GI irAE) and skin rash, which are managed by treatment guidelines. Nevertheless, predictive biomarkers that can help identify patients more likely to develop these irAEs could enhance the management of these toxicities.MethodsTo identify candidate predictive biomarkers associated with GI irAEs, gene expression profiling was performed on whole blood samples from 162 advanced melanoma patients at baseline, 3 and 11xa0weeks after the start of ipilimumab treatment in two phase II clinical trials (CA184004 and CA184007). Overall, 49 patients developed Grade 2 or higher (grade 2+) GI irAEs during the course of treatment. A repeated measures analysis of variance (ANOVA) was used to evaluate the differences in mean expression levels between the GI irAE and No-GI irAE groups of patients at the three time points.ResultsIn baseline samples, 27 probe sets showed differential mean expression (≥ 1.5 fold, P ≤ 0.05) between the GI irAE and No-GI irAE groups. Most of these probe sets belonged to three functional categories: immune system, cell cycle, and intracellular trafficking. Changes in gene expression over time were also characterized. In the GI irAE group, 58 and 247 probe sets had a ≥ 1.5 fold change in expression from baseline to 3 and 11xa0weeks after first ipilimumab dose, respectively. In particular, on-treatment expression increases of CD177 and CEACAM1, two neutrophil-activation markers, were closely associated with GI irAEs, suggesting a possible role of neutrophils in ipilimumab-associated GI irAEs. In addition, the expression of several immunoglobulin genes increased over time, with greater increases in patients with grade 2+ GI irAEs.ConclusionsGene expression profiling of peripheral blood, sampled before or early in the course of treatment with ipilimumab, resulted in the identification of a set of potential biomarkers that were associated with occurrence of GI irAEs. However, because of the low sensitivity of these biomarkers, they cannot be used alone to predict which patients will develop GI irAEs. Further investigation of these biomarkers in a larger patient cohort is warranted.

Association Between ADAMTS1 Matrix Metalloproteinase Gene Variation, Coronary Heart Disease, and Benefit of Statin Therapy

Objective—The purpose of this study was to investigate the association between the Ala227Pro polymorphism in the ADAMTS1 metalloproteinase gene and coronary heart disease and benefit from statin therapy in 2 independent cohorts. Methods and Results—The frequency of the ADAMTS1 227Pro minor allele was 0.24 in 2421 male subjects from CARE, a randomized trial of pravastatin versus placebo. In the placebo arm, homozygotes (6.3% of study population) had a significantly increased risk of fatal coronary disease or nonfatal myocardial infarction (D/MI) compared with noncarriers (OR 2.12, 95% CI 1.07 to 4.19, P=0.03), and in the entire study the benefit of pravastatin in reducing the risk of D/MI was greater in these subjects (OR 0.21, 95% CI 0.06 to 0.69) than in heterozygotes (OR 0.74, 95% CI 0.48 to 1.14) or noncarriers (OR 0.99, 95% CI 0.68 to 1.42; Pinteraction=0.044). Results were tested in 1565 male subjects from WOSCOPS, also a randomized trial of pravastatin versus placebo. Similar to the results in CARE, in the placebo arm subjects homozygous for the minor allele were at increased risk of D/MI (OR 1.72, P=0.052) and in the entire study the benefit of pravastatin in reducing D/MI was greater in these subjects (OR 0.24, 95% CI 0.09 to 0.68) than in heterozygotes (OR 0.73, 95% CI 0.48 to 1.11) or noncarriers (OR 0.65, 95% CI 0.20 to 2.09) (Pinteraction=0.029). Conclusions—In men not on pravastatin, those homozygous for the 227Pro allele of ADAMTS1 have a nearly 2-fold increased risk of coronary heart disease events compared with noncarriers. In this high-risk group, treatment with pravastatin is highly efficacious, reducing the odds of fatal coronary disease or nonfatal MI by approximately 75%, as compared with 25% in noncarriers or heterozygotes.

Asp92Asn polymorphism in the myeloid IgA Fc receptor is associated with myocardial infarction in two disparate populations: CARE and WOSCOPS.

Objective—Statins reduce inflammation and risk of myocardial infarction (MI). Because the myeloid IgA Fc receptor encoded by FCAR mediates inflammation, we hypothesized that the FCAR Asp92Asn polymorphism is associated with risk of MI and that this risk would be modified by pravastatin. Methods and Results—In the placebo arm of the Cholesterol and Recurrent Events (CARE) study, male carriers of the 92Asn allele had an adjusted hazard ratio for incident MI of 1.68 (95% CI 1.10 to 2.57); relative risk reduction by pravastatin was 69% in carriers and 12% in noncarriers (Pinteraction=0.007). In the placebo arm of the all-male West of Scotland Coronary Prevention Study (WOSCOPS), carriers had an adjusted odds ratio for incident coronary heart disease (CHD) of 1.46 (90% CI 1.05 to 2.03); for pravastatin compared with placebo treatment, the adjusted odds ratios were 0.55 (95% CI 0.32 to 0.93) in carriers and 0.65 (95% CI 0.51 to 0.83) in noncarriers (Pinteraction=0.55). Conclusions—Carriers of 92Asn had increased risk of MI in CARE and increased odds of CHD in WOSCOPS. Pravastatin significantly reduced risk in carriers in both CARE and WOSCOPS. A genotype by treatment interaction was observed in CARE but not in WOSCOPS.

79 Ipilimumab-Related Colitis in Patients with Advanced Melanoma Receiving Ipilimumab Therapy: Histopathologic and Serologic Characterization

Background: Natural history observations in early onset IBD have prompted the increasing use of anti-TNFα therapy. Inter-individual variation, however, is seen in efficacy outcomes. These differences may be explained in part by genetic variability as it relates to disease pathogenesis or directed to the mechanism of action of these therapies. Recent GWA studies in IBD have increased our understanding of the genetic susceptibility to IBD and provide insight regarding the various mechanisms of inflammation. We hypothesize that interindividual differences in therapeutic outcomes to anti-TNFαmay be associated with IBD susceptibility genes. Aim: Test associations of GWA identified IBD susceptibility loci (34 SNPs) with infliximab (IFX) responsiveness in pediatric IBD patients. Methods: Complete follow up and GWAS data was available on 63 children receiving IFX. Harvey Bradshaw index (HBI) was used to calculate disease activity. Outcomes were primary nonresponse: no change or increase in HBI at week 10; and secondary loss of response: drop in HBI by >3 points at week 10 (response) and then increase to or above baseline HBI week 14 or later. Chi square testing examined the association between 34 SNPs and IFX responsiveness. Time to loss of response was calculated using Kaplan Meier analysis. Results: Six SNPs (Table 1) were associated with primary non-response (p < 0.05). There were 5 different SNPs (Chromosome) associated with loss of response; rs11174631 (12q12); OR =10.6, p= 0.03; rs8049439 (16p11); OR = 3.8, p= 0.03, rs2456449 (8q24); OR= 4.8, p = 0.02, rs10044354 (5q15); OR = 3.8, p = 0.03, rs6908425 (6p22); OR = 4.1, p = 0.03. Of these 5 SNPs, 4 were also associated with the time to loss of response (median 9 months): rs11174631 (p= 0.03), rs2456449 (p = 0.03), rs10044354 (p = 0.04), rs6908425 (p = 0.02). Conclusion: These findings suggest that there may be different genetic predictors and perhaps biological explanations for primary non response vs. secondary loss of response. Replication studies are currently underway. Defining predictors of response to anti-TNFα will allow the identification of patients with a high probability of response before initiating therapy so to negate exposure to ineffective therapies and protect patients from treatment related serious adverse events. Primary Non Response