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These results from a large, prospective, observational study suggest that continued vascular endothelial growth factor inhibition with bevacizumab beyond initial PD could play an important role improving the overall success of therapy for patients who have mCRC.

PurposeSonic hedgehog (SHH), an activating ligand of smoothened (SMO), is overexpressed in > 70% of pancreatic cancers (PCs). We investigated the impact of vismodegib, an SHH antagonist, plus gemcitabine (GV) or gemcitabine plus placebo (GP) in a multicenter phase Ib/randomized phase II trial and preclinical PC models.Patients and MethodsPatients with PC not amenable to curative therapy who had received no prior therapy for metastatic disease and had Karnofsky performance score ≥ 80 were enrolled. Patients were randomly assigned in a one-to-one ratio to GV or GP. The primary end point was progression-free-survival (PFS). Exploratory correlative studies included serial SHH serum levels and contrast perfusion computed tomography imaging. To further investigate putative biologic mechanisms of SMO inhibition, two autochthonous pancreatic cancer models (KrasG12D; p16/p19fl/fl; Pdx1-Cre and KrasG12D; p53R270H/wt; Pdx1-Cre) were studied.ResultsNo safety issues were identified in the phase Ib portion (n = 7), and the phase II study enrolled 106 evaluable patients (n = 53 in each arm). Median PFS was 4.0 and 2.5 months for GV and GP arms, respectively (95% CI, 2.5 to 5.3 and 1.9 to 3.8, respectively; adjusted hazard ratio, 0.81; 95% CI, 0.54 to 1.21; P = .30). Median overall survival (OS) was 6.9 and 6.1 months for GV and GP arms, respectively (95% CI, 5.8 to 8.0 and 5.0 to 8.0, respectively; adjusted hazard ratio, 1.04; 95% CI, 0.69 to 1.58; P = .84). Response rates were not significantly different. There were no significant associations between correlative markers and overall response rate, PFS, or OS. Preclinical trials revealed no significant differences with vismodegib in drug delivery, tumor growth rate, or OS in either model.ConclusionThe addition of vismodegib to gemcitabine in an unselected cohort did not improve overall response rate, PFS, or OS in patients with metastatic PC. Our preclinical and clinical results revealed no statistically significant differences with respect to drug delivery or treatment efficacy using vismodegib.

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The combination of bevacizumab plus gemcitabine is active in advanced pancreatic cancer patients. Additional study is warranted. A randomized phase III trial of gemcitabine plus bevacizumab versus gemcitabine plus placebo is ongoing in the Cancer and Leukemia Group B.

Background. The Bevacizumab Regimens' Investigation of Treatment Effects (BRiTE) study is a prospective, observational cohort study designed to elucidate safety and effectiveness outcomes associated with bevacizumab combined with chemotherapy as used in clinical practice for first-line treatment of metastatic colorectal cancer (mCRC).Patients and Methods. Baseline characteristics, prespecified bevacizumab-related adverse events, and ef-

Background The epidermal growth factor receptor (EGFR) is a validated target in squamous cell carcinoma of the head and neck but in patients with recurrent or metastatic disease, EGFR targeting agents have displayed modest efficacy. Vascular endothelial growth factor (VEGF) mediated angiogenesis has been implicated as a mechanism of resistance to anti-EGFR therapy. This study combined an EGFR inhibitor, erlotinib, with an anti-VEGF antibody, bevacizumab. Methods This multi-institutional phase I/II study enrolled patients with recurrent or metastatic squamous cell carcinoma of the head and neck to receive erlotinib (150 mg daily) and bevacizumab in escalating dose cohorts. The primary objectives in the phase I and II portions, respectively, were to determine the maximum tolerated dose and dose-limiting toxicity of bevacizumab when administered with erlotinib and to determine the objective response rate and time to disease progression. Pre-treatment serum and tissues were collected and analyzed by Enzyme-Linked ImmunoSorbent Assay and immunofluorescence quantitative laser analysis, respectively. This study was registered with ClinicalTrials.gov, number NCT00055913. Findings The phase I portion enrolled 10 subjects in three successive cohorts without dose-limiting toxicity observed. An additional 46 subjects were enrolled at the phase II dose (bevacizumab 15 mg/kg every 3 weeks). The most common toxicities of any grade were rash and diarrhea (41 and 16 of 48 subjects, respectively). Three patients experienced serious bleeding events. The observed response rate was 15% with 4 complete responses (CR) allowing rejection of the null hypothesis. The median overall and progression-free survival (PFS) durations were 7.1 (95% Confidence Interval: 5.7 to 9.0) and 4.1 (95% Confidence Interval: 2.8 to 4.4) months, respectively. Higher ratios of phosphorylated over total VEGF receptor-2 and EGFR in pre-treatment biopsies were associated with CR (0.7043 vs. 0.3857, p=0.036 and 0.949 vs. 0.332, p=0.036, respectively) and tumor shrinkage (p=0.007 and p=0.008, respectively) in a subset of 11 subjects with available tissue. Interpretation The combination of erlotinib and bevacizumab is well tolerated in recurrent or metastatic squamous cell carcinoma of the head and neck. Some patients appear to derive a sustained benefit and complete responses were associated with expression of putative targets in pre-treatment tumor tissue.

Purpose: African Americans have higher incidence and poorer response to lung cancer treatment compared with Caucasians. However, the underlying molecular mechanisms for the significant ethnic difference are not known. The present study examines the ethnic differences in the type and frequency of MET proto-oncogene (MET) mutation in lung cancer and correlated them with other frequently mutated genes such as epidermal growth factor receptor (EGFR), KRAS2, and TP53. Experimental Design: Using tumor tissue genomic DNA from 141 Asian, 76 Caucasian, and 66 African American lung cancer patients, exons coding for MET and EGFR were PCR amplified, and mutations were detected by sequencing. Mutation carriers were further screened for KRAS2 and TP53 mutations. Functional implications of important MET mutations were explored by molecular modeling and hepatocyte growth factor binding studies. Results: Unlike the frequently encountered somatic mutations in EGFR, MET mutations in lung tumors were germline. MET-N375S, the most frequent mutation of MET, occurred in 13% of East Asians compared with none in African Americans. The frequency of MET mutations was highest among male smokers and squamous cell carcinoma. The MET-N375S mutation seems to confer resistance to MET inhibition based on hepatocyte growth factor ligand binding, molecular modeling, and apoptotic susceptibility to MET inhibitor studies. Conclusions: MET in lung cancer tissues contained nonsynonymous mutations in the semaphorin and juxtamembrane domains but not in the tyrosine kinase domain. All the MET mutations were germline. East Asians, African-Americans, and Caucasians had different MET genotypes and haplotypes. MET mutations in the semaphorin domain affected ligand binding. (Clin Cancer Res 2009;15(18):5714-23) Lung cancer is a difficult disease to treat and is the most commonly diagnosed form of cancer, and its ravages on human health is underscored by the fact that there are over 213,000 new cases every year in the United States alone. Despite significant advances in treatments over the past two decades, only 15% of lung cancer patients survive for 5 years or longer (1). However, one of the most interesting and intriguing facts that has emerged from recent ethnic studies is that African Americans