Shethah Morgan

Antitumor Effects and Biomarkers of Activity of AZD0530, a Src Inhibitor, in Pancreatic Cancer

Purpose: To determine the efficacy of AZD0530, an orally active small molecule Src inhibitor, in human pancreatic cancer xenografts and to seek biomarkers predictive of activity. Experimental Design: Sixteen patient-derived pancreatic cancer xenografts from the PancXenoBank collection at Johns Hopkins were treated with AZD0530 (50 mg/kg/day, p.o.) for 28 days. Baseline gene expression profiles of differently expressed genes in 16 tumors by Affymetrix U133 Plus 2.0 gene array were used to predict AZD0530 sensitivity in an independent group of eight tumors using the K-Top Scoring Pairs (K-TSP) method. Results: Three patient tumors of 16 were found to be sensitive to AZD0530, defined as tumor growth <50% compared with control tumors (100%). Western blot and/or immunohistochemistry results showed that AZD0530 administration resulted in the down-regulation of Src, FAK, p-FAK, p-paxillin, p-STAT-3, and XIAP in sensitive tumor xenografts compared with control tumors. The K-TSP classifier identified one gene pair (LRRC19 and IGFBP2) from the 16 training cases based on a decision rule. The classifier achieved 100% and 83.3% of sensitivity and specificity in an independent test set that consists of eight xenograft cases. Conclusions: AZD0530 treatment significantly inhibits the tumor growth in a subset of human pancreatic tumor xenografts. One gene pair (LRRC19 and IGFBP2) identified by the K-TSP classifier has high predictive power for AZD0530 sensitivity, suggesting the potential for this gene pair as biomarker for pancreatic tumor sensitivity to AZD0530.

Comparison of KRAS Mutation Assessment in Tumor DNA and Circulating Free DNA in Plasma and Serum Samples

Testing for mutations in the KRAS oncogene for patients with metastatic colorectal cancer (mCRC) is generally performed using DNA from formalin-fixed paraffin-embedded tumor tissue; however, access to specimens can be limited and analysis challenging. This study assessed the identification of KRAS mutations in circulating free DNA (cfDNA) using a commercially available KRAS polymerase chain reaction (PCR) kit. Matched plasma, serum and tumor samples were available from 71 patients with mCRC who had received prior therapy but whose disease progressed following therapy. Yields of cfDNA from plasma and serum samples were comparable. Analyses were successful in 70/71 plasma-extracted samples (specificity: 97%, sensitivity: 31%) and 67/71 serum-extracted samples (specificity: 100%, sensitivity: 25%). This study demonstrates that KRAS mutations can be detected in cfDNA using a commercially available KRAS PCR kit, confirming cfDNA as a potential alternative source of tumor DNA in a diagnostic setting if access to archival tumor specimens is limited.

Correlation of Lactate Dehydrogenase Isoenzyme Profile With Outcome in Patients With Advanced Colorectal Cancer Treated With Chemotherapy and Bevacizumab or Cediranib: Retrospective Analysis of the HORIZON I Study

INTRODUCTION Bevacizumab improves outcome for patients with advanced colorectal cancer (CRC) when added to chemotherapy. The HORIZON I trial resulted in similar outcome with bevacizumab or cediranib, a small-molecule tyrosine kinase inhibitor of vascular endothelial growth factor (VEGF) receptor, as treatment of advanced CRC. The spectrum of lactate dehydrogenase (LDH) isoenzyme expression was examined in serum samples of HORIZON I participants to identify biomarkers predictive of efficacy of VEGF pathway inhibitors. MATERIALS AND METHODS Total LDH levels, as well as LDH isoenzyme levels in frozen baseline serum samples, were retrospectively evaluated. Total LDH serum levels measured during the study, progression-free survival (PFS), and overall survival (OS) were available from the HORIZON I study data. RESULTS Total LDH levels measured in the frozen serum samples correlated with those measured in fresh samples. The expected reciprocal correlation was found between hypoxic and oxic LDH isoenzymes. High total LDH correlated with shorter PFS, and high hypoxia-related LDH isoenzymes correlated with shorter PFS and OS. The difference in outcome of the cediranib-treated patients vs. those treated with bevacizumab was not substantially different in the various LDH isoform expression subgroups. In patients with a hypoxic LDH pattern of expression, there was a nonsignificant trend of better outcome in cediranib-treated patients. CONCLUSION Evaluation of total LDH and its isoforms in frozen serum samples is feasible. High total LDH and high hypoxic LDH isoenzymes were associated with poor prognosis. Further studies are needed to evaluate the predictive value of LDH isoenzyme expression pattern for VEGF-pathway inhibition efficacy.

Biomarker-Based Phase II Trial of Savolitinib in Patients With Advanced Papillary Renal Cell Cancer

Purpose Patients with advanced papillary renal cell carcinoma (PRCC) have limited therapeutic options. PRCC may involve activation of the MET pathway, for example, through gene amplification or mutations. Savolitinib (AZD6094, HMPL-504, volitinib) is a highly selective MET tyrosine kinase inhibitor. We report results of a single-arm, multicenter, phase II study evaluating the safety and efficacy of savolitinib in patients with PRCC according to MET status. Patients and Methods Patients with histologically confirmed locally advanced or metastatic PRCC were enrolled and received savolitinib 600 mg orally once daily. MET-driven PRCC was defined as any of the following: chromosome 7 copy gain, focal MET or HGF gene amplification, or MET kinase domain mutations. Efficacy was assessed according to MET status. Safety, toxicity, and patient-reported health-related quality-of-life outcomes were assessed in all patients. Results Of 109 patients treated, PRCC was MET driven in 44 (40%) and MET independent in 46 (42%); MET status was unknown in 19 (17%). MET-driven PRCC was strongly associated with response; there were eight confirmed partial responders with MET-driven disease (18%), but none with MET-independent disease ( P = .002). Median progression-free survival for patients with MET-driven and MET-independent PRCC was 6.2 months (95% CI, 4.1 to 7.0 months) and 1.4 months (95% CI, 1.4 to 2.7 months), respectively (hazard ratio, 0.33; 95% CI, 0.20 to 0.52; log-rank P < .001). The most frequent adverse events associated with savolitinib were nausea, fatigue, vomiting, and peripheral edema. Conclusion These data show activity and tolerability of savolitinib in the subgroup of patients with MET-driven PRCC. Furthermore, molecular characterization of MET status was more predictive of response to savolitinib than a classification based on pathology. These findings justify investigating savolitinib in MET-driven PRCC.

KRAS mutations are associated with inferior clinical outcome in patients with metastatic colorectal cancer, but are not predictive for benefit with cediranib.

PURPOSE The prognostic potential of KRAS mutations in advanced colorectal cancer (CRC) patients and the impact of KRAS mutation status on the effectiveness of chemotherapy or vascular endothelial growth factor (VEGF) signalling inhibitor therapy remain unclear. KRAS mutation status was evaluated retrospectively as a potential prognostic/predictive marker of clinical outcomes using tumour samples from patients with metastatic CRC receiving cediranib or placebo plus FOLFOX/XELOX in a Phase III trial (HORIZON II; NCT00399035). METHODS KRAS codon 12 and 13 mutation analyses were performed using a commercially available, allele-specific, amplification refractory mutation system (ARMS)-based polymerase chain reaction (PCR) assay. Retrospective analyses of progression-free survival (PFS) and overall survival (OS) according to KRAS mutation status were performed for patients randomised to cediranib 20mg or placebo. RESULTS KRAS status was determined in 599/1076 patients (cediranib 20mg, n=285/502; cediranib 30 mg, n=110/216; placebo, n=204/358). Baseline characteristics were similar across KRAS mutant (n=258; 24.0%), wild-type (n=341; 31.7%) and status unknown (n=477; 44.3%) groups. There was a trend towards improved PFS and OS in the wild-type versus mutant subgroups independent of treatment (cediranib 20 mg and placebo: PFS hazard ratio (HR)=0.85 [median PFS: wild-type=8.5 months; mutant=8.3 months]; OS HR=0.71 [median OS: wild-type=20.9 months; mutant=16.9 months]). Treatment effects were similar between KRAS subgroups for cediranib 20mg versus placebo (PFS: wild-type HR=0.78, mutant HR=0.82; OS: wild-type HR=0.92, mutant HR=1.01). CONCLUSION Data from this large randomised Phase III study show that KRAS codon 12/13 mutations have negative prognostic value in metastatic CRC patients receiving treatment with FOLFOX/XELOX, but KRAS mutation status is not predictive of treatment benefit with cediranib, using PFS or OS.

Leptin, BMI, and a Metabolic Gene Expression Signature Associated with Clinical Outcome to VEGF Inhibition in Colorectal Cancer.

VEGF (vascular endothelial growth factor) signaling inhibitors are widely used in different cancer types; however, patient selection remains a challenge. Analyses of samples from a phase III clinical trial in metastatic colorectal cancer testing chemotherapy versus chemotherapy with the small molecule VEGF receptors inhibitor cediranib identified circulating leptin levels, BMI, and a tumor metabolic and angiogenic gene expression signature associated with improved clinical outcome in patients treated with cediranib. Patients with a glycolytic and hypoxic/angiogenic profile were associated with increased benefit from cediranib, whereas patients with a high lipogenic, oxidative phosphorylation and serine biosynthesis signature did not gain benefit. These findings translated to pre-clinical tumor xenograft models where the same metabolic gene expression profiles were associated with in vivo sensitivity to cediranib as monotherapy. These findings suggest a link between patient physiology, tumor biology, and response to antiangiogenics, which may guide patient selection for VEGF therapy in the future.

Abstract 4811: Soluble biomarkers identify mCRC patients subgroups showing increased benefit from the VEGF signaling inhibitor cediranib in combination with chemotherapy

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Identifying potential predictive biomarkers differentiating sensitivity/resistance to VEGF signaling inhibitors (VEGFi) will enhance use of these therapies. We used >580 pre and on-treatment serum samples and 259 tumours diagnostic biopsies from mCRC patients enrolled in a Phase III trial (HORIZON II) treated with chemotherapy ± cediranib(a VEGFi), to screen the potential predictive value of multiple serum proteins and tumour genes. At baseline leptin was the most significant marker associated with OS of patients treated with chemo-ced (Pinteraction 30) showed improved OS when treated with chemo-ced compared to non-obese patients (HR=0.55, 0.36-0.85, p=0.008). In the same patients, we identified two gene expression signatures associated with benefit on chemo-ced. Patients characterized by a high expression of GAHGL (Glucose metabolism, Angiogenesis, Hypoxia, Glutamine metabolism, Leptin signaling) (Pinteraction=0.028) and low expression of LOPS (Lipid metabolism, Oxidative activity, Proliferation and Serine synthesis) gene signature (Pinteraction=0.002) had improved OS in chemo-ced treated patients. Serum leptin concentration was found positively correlated with expression of genes involved in GAHGL in patients. In addition a baseline signature (BS) of 47 biomarkers including VEGFA, VEGFD, VEGFR2, VEGFR3 and TIE-2, defined two distinct subgroups of patients. Patients treated with chemotherapy plus cediranib who had ‘high’ BS had shorter PFS (HR=1.82, p=0.003) than patients with ‘low’ BS. This BS had no effect on PFS of the patients treated with chemotherapy plus placebo. Finally, we identified a profile of 16 pharmacodynamic (PD) proteins on treatment associated with PFS (HR=0.58, p<0.001) and OS (HR=0.52, p<0.001) in patients treated with chemotherapy plus cediranib. This PD profile had no effect on PFS and OS in patients treated with chemotherapy plus placebo. This work provides original candidate biomarkers to select patients most likely to benefit from VEGFi therapies. Citation Format: Aurelien J.C. Pommier, Stuart Spencer, Shethah Morgan, Chris Womack, Juliane M. Jurgensmeier, Susan Critchlow, Simon T. Barry. Soluble biomarkers identify mCRC patients subgroups showing increased benefit from the VEGF signaling inhibitor cediranib in combination with chemotherapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4811. doi:10.1158/1538-7445.AM2014-4811