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Western blot analysis in responsive PDX model (LI0612) after 14 days treatment. Total and phosphorylated levels of the indicated proteins were evaluated to assess the effects of AMG 337 on MET signaling. Five to twelve PDX samples were processed for each group.

Overall Survival Comparison Between MET Subgroups by Treatment Disposition

The second-generation proteasome inhibitor carfilzomib produces superior outcomes in relapsed or refractory multiple myeloma (MM). We conducted a single-arm trial of twice-weekly carfilzomib (27 mg/m2)-dexamethasone (Kd27) for relapsed and refractory MM in China. Kd27 was administered in 28-day cycles to 123 patients previously treated with ≥ 2 other regimens, including treatment with bortezomib and an immunomodulatory drug, and refractory to their most recent therapy. Overall response rate (ORR) was the primary endpoint; progression-free survival (PFS) and overall survival (OS) were key secondary endpoints. Primary analysis was conducted when all patients received ≥ 6 cycles of Kd27 or discontinued Kd27. Median age was 60 years; median number of prior regimens was 4; 74% were refractory to proteasome inhibitors and immunomodulatory drugs. ORR was 35.8% (95% CI 27.3–44.9), median PFS was 5.6 (95% CI 4.6–6.5) months, and median OS was 16.6 (95% CI 12.2–NE) months. Grade ≥ 3 adverse events (AEs) occurred in 76.4% of patients. Grade ≥ 3 AEs of interest included hypertension (13.8%), acute renal failure (3.3%), cardiac failure (0.8%), ischemic heart disease (0.0%), and peripheral neuropathy (0.0%); 5.7% of patients discontinued carfilzomib due to AEs. Carfilzomib–dexamethasone produced a clinically meaningful response without new safety findings in Chinese patients with previously treated MM. Trial registration: NCT03029234.

Introduction As a result of the negative impact of bone metastases on patient quality of life, it is important to identify patients at increased risk of skeletal-related events (SREs). Biochemical markers produced by osteoblasts and osteoclasts may provide an early indicator of treatment response to antiresorptive therapy. We aimed to explore the relationship between change in the urinary bone turnover marker cross-linked N-terminal telopeptide of type 1 collagen (uNTX) at the earliest time of steady state and risk of SREs. Methods A comprehensive search of eight bibliographic databases and two trial registries was conducted (June 2017). We included randomized controlled trials of adults (≥18 years old) with bone metastases from solid tumors (including breast, lung, prostate) or bone lesions from multiple myeloma that compared denosumab or bisphosphonate(s) with each other or a placebo. Meta-analyses were used to evaluate the relationship between uNTX and SREs. The primary outcomes were based on uNTX at week 13 and SREs in those studies. Results Seventeen studies (12,130 patients) were included. The analysis results indicated a positive association between uNTX reduction, measured by the between-group difference of the natural logarithm of the ratio between uNTX at week 13 and baseline, and SRE risk reduction, measured by the natural logarithm of the hazard ratio (HR) for time to first SRE between the two groups (uNTX effect on SRE risk, defined as SRE HR increase corresponding to one unit smaller in the magnitude of uNTX reduction: 0.3560, 95% confidence interval 0.0249–0.6871; P = .0390, R2 = 0.7360). Results were similar for studies that reported change in uNTX from baseline to week 13 and to later than week 13. The limitation of this review is that it depends on how comprehensive study data were that could be included in the meta-regression. Conclusions Our findings support a positive relationship between reduction of bone turnover markers at the earliest time of steady state and reduction in longer-term risk of SREs., Highlights • Identifying those at risk of skeletal-related events is key to ameliorate the impact of bone metastases on quality-of-life. • uNTX and bone-specific alkaline phosphatase are candidate surrogate markers for skeletal-related events. • We report a relationship between reduced markers of bone turnover and reduced longer-term risk of skeletal-related events.

Aims This study aimed to predict time course of bone mineral density (BMD) by using corresponding response of bone turnover markers (BTMs) in women with postmenopausal osteoporosis under antiresorptive treatments. Methods Data were extracted from literature searches in accessible public database. Time courses of percent change from baseline in serum C-telopeptide of type 1 collagen (sCTX) and N-telopeptide of type 1 collagen were described by complex exponential onset models. The relationship between BTM changes and BMD changes at lumbar spine and total hip was described using a multiscale indirect response model. Results The dataset included 41 eligible published trials of 5 US-approved antiresorptive agents (alendronate, ibandronate, risedronate, zoledronic acid and denosumab), containing over 28 800 women with postmenopausal osteoporosis. The time courses of BTM changes for different drugs were differentiated by maximal effect and onset rate in developed model, while sCTX responses to zoledronic acid and denosumab were captured by another model formation. Furthermore, asynchronous relationship between BTMs and BMD was described by a bone remodelling-based semimechanistic model, including zero-order production and first-order elimination induced by N-telopeptide of type 1 collagen and sCTX, separately. After external and informative validations, the developed models were able to predict BMD increase using 1-year data. Conclusion This exploratory analysis built a quantitative framework linking BTMs and BMD among antiresorptive agents, as well as a modelling approach to enhance comprehension of dynamic relationship between early and later endpoints among agents in a certain mechanism of action. Moreover, the developed models can offer predictions of BMD from BTMs supporting early drug development.

Aberrant hepatocyte growth factor (HGF)/MET signaling has been implicated in hepatocarcinogenesis, suggesting that MET may serve as an attractive therapeutic target in hepatocellular carcinoma. We sought to investigate the in vitro and in vivo antitumor activity of AMG 337, a potent and highly selective small molecule MET kinase inhibitor, in preclinical models of hepatocellular carcinoma. The antiproliferative activity of AMG 337 was evaluated across a panel of hepatocellular carcinoma cell lines in a viability assay. Daily oral administration was used to evaluate the in vivo antitumor activity of AMG 337 in two patient-derived xenograft (PDX) models of hepatocellular carcinoma (LI0612 and LI1078). AMG 337 exerted potent antiproliferative activity against 2 of 40 hepatocellular carcinoma cell lines, namely, MHCC97H (IC50, 0.015 μmol/L) and HCCLM3 (IC50, 0.025 μmol/L). Both sensitive cell lines showed MET amplification (MET/CEN-7 >2.0) assessed by FISH, and high MET expression (3+ IHC) assessed by IHC. AMG 337 potently inhibited p-MET in all cell lines with detectable levels of total MET. However, the dose-dependent inhibition of downstream effectors of HGF/MET signaling, including p-GAB1, p-AKT, and p-ERK, was limited to those cell lines sensitive to AMG 337 in a viability assay (MHCC97H and HCCLM3). AMG 337 significantly inhibited tumor growth at all doses tested in the MET-amplified and MET-high–expressing hepatocellular carcinoma PDX model LI0612 and had no effect on tumor growth in the non-MET–amplified and MET-low–expressing hepatocellular carcinoma PDX model LI1078. AMG 337 represents a promising and novel therapeutic strategy for targeting hepatocellular carcinomas with a dependence on HGF/MET signaling. Mol Cancer Ther; 15(6); 1227–37. ©2016 AACR.

MET and its sole ligand, hepatocyte growth factor (HGF), are promising targets in gastric and gastroesophageal junction cancer. We evaluated whether MET protein expression or MET gene amplification is prognostic for overall survival (OS) in Chinese patients with advanced gastric or gastroesophageal junction cancer. Archival formalin-fixed, paraffin-embedded tumor samples from patients with unresectable locally advanced or metastatic gastric or gastroesophageal junction cancer enrolled in clinical trials at Peking University Cancer Hospital from 2008 to 2010 were assessed for MET and phospho-MET (p-MET) expression by immunohistochemistry and MET amplification by FISH. MET-positive expression was defined as membrane protein staining in ≥25% of tumor cells. MET amplification was defined as MET:centromere 7 ratio >2.0. We tested the association of MET status with clinical characteristics and OS, and also evaluated the association between expression and amplification. One hundred sixty-eight patients were eligible. Of the evaluable samples, 53 of 137 (39%) were MET positive, eight of 134 (6%) were p-MET positive, and eight of 113 (7%) were MET amplified. Neither MET expression nor MET amplification were associated with clinical characteristics, except Lauren classification (P = 0.04); MET amplification was associated with diffuse type. No significant OS difference was observed between MET-positive and MET-negative populations, regardless of first-line chemotherapy received. In 95 evaluable patients, MET expression was significantly associated with MET amplification (P < 0.001); all MET-amplified tumor samples showed some MET expression. In 96 evaluable patients, p-MET positivity was significantly associated with MET amplification (P < 0.001). Further evaluation in larger and independent sample sets is warranted to confirm our findings. Mol Cancer Ther; 14(11); 2634–41. ©2015 AACR.

This study aims to evaluate patient perceptions of subcutaneous denosumab or oral alendronate in postmenopausal women with or at risk for osteoporosis and how these perceptions influence adherence.Postmenopausal women with low bone mass were randomized to denosumab 60 mg every 6 months for 1 year (treatment period 1 [TP1]) followed by alendronate 70 mg once weekly for 1 year (treatment period 2 [TP2]), or vice versa. Beliefs about Medicines Questionnaire data were collected at baseline and at 6, 12, 18, and 24 months; a necessity-concerns differential (NCD) was calculated for each time point. Logistic regression analyses were performed to evaluate the influences of baseline characteristics on nonadherence.Participants included 250 women (alendronate/denosumab, n = 124; denosumab/alendronate, n = 126). During TP1, the NCD at month 6 was higher with denosumab than with alendronate (P = 0.0076). In TP2, the NCD was higher for women switched to denosumab than for women switched to alendronate at 6 months (P = 0.0126) and 12 months (P = 0.4605). Denosumab was preferred to alendronate regardless of treatment sequence (P0.0001). Covariate analysis revealed that higher TP2 baseline necessity scores were associated with lower odds of nonadherence (P = 0.0055), whereas higher concerns about medication scores were associated with higher odds of nonadherence (P = 0.0247). Higher NCD scores were also associated with lower odds of nonadherence (P = 0.0015).Participants preferred denosumab to alendronate while on treatment and had more positive perceptions of denosumab than alendronate. These perceptions were associated with better adherence.

Introduction B cell acute lymphoblastic leukemia (B-ALL) is a severe disease caused by malignant transformation and uncontrolled proliferation of immature B lymphocytes. Blinatumomab, a Bi-specific T cell engager (BiTE®) combining the VH and VL domains of two antibodies against human CD19 and CD3, has been approved by U.S. Food and Drug Administration (FDA) for the treatment of Philadelphia chromosome negative (Ph-) relapsed or refractory B-ALL in 2014, and recently Philadelphia chromosome-positive (Ph+) B-ALL. Blinatumomab brings killer T and target B cells into close proximity, activating patients' autologous T cells to kill both normal and malignant B cells via mechanisms such as cytolytic immune synapse formation and inflammatory cytokine production. Clinical trials have shown that there are still patients refractory to blinatumomab. It is thus of great importance to understand the resistance mechanisms and search for biomarkers for patient selection. Methods and Results In this study, we used Mass cytometry-based immunophenotyping and Luminex based multiple protein quantitation, to search for biomarkers correlated with the killing capacity of blinatumomab. First, we collected PBMCs from 12 B-ALL patients for an in vitro killing assay, focusing on the quantity and quality profiling of T cells. PBMCs were used as the effector cells and NALM-6 as the target cells. The final effector to target (E/T) ratio is 10:1. Blinatumomab were added to the co-cultured cells (final concentration 10 ng/mL) for 18hrs. A 5% specific lysis of NALM-6 was used as cut-off threshold. Samples with specific killing above 5% were classified as "positive" for blinatumomab response, and below 5% as "negative". Among the patients analyzed, 4 out of 12 patients (33.3%) showed apparent and specific lysis of NALM6 leukemia cells, while the remaining samples showed no obvious effect. This divergent killing effect of blinatumomab with the presence of PBMCs from different donors may reflect the differentiated treatment response in B-ALL patients. Concurrently we immunophenotyped each patient's PBMCs by Mass cytometry with a panel of antibodies for surface lineage markers and intracellular effector molecules and cytokines /chemokines. Unsupervised clustering showed that a panel of T-cell associated biomarkers highly significantly correlated with B-ALL cell response to blinatumomab (p=0.001, R=0.839). This panel of biomarkers included T cell markers of CD45, CD3 and CD4; cytolytic proteins of Perforin and GranzymeB; cytokines of IL-2, INFγ and TNFα; and chemokine CCL4 (also known as MIP-1b). In a Luminex analysis examining multiple proteins accumulating in the culture supernatant from the in vitro killing assay, the top biomarkers identified by Mass cytometry also showed significant response to blinatumomab at different time points (12, 24 and 48 hrs). They included TNF-α, CCL4, IL-2, INFγ and Granzyme B. Furthermore, released CCL4 at 24 and 48 hrs and INFγ at 48 hrs significantly correlated with blinatumomab mediated cytotoxicity. Conclusion In summary, the immunophenotyping and multiplexed protein measurement by Mass cytometry and Luminex assay identified key biomarkers that may correlate with blinatumomab-mediated killing of B-ALL leukemia cells. The biomarker panel reflected the importance of primed T cell activation, associated key cytokine/chemokine as well as the consequent cytolytic protein release in the overall response to blinatumomab. Thus, in vitro biomarker profiling focusing on T cell status with these key molecules may facilitate patient selection and predict the response to the immunotherapy. Disclosures Fu: Amgen: Research Funding.

We show that in the case of Fay–Herriot model for small area estimation, there is an estimator of the variance of the random effects so that the resulting EBLUP is the best in the sense that it minimizes the leading term in the asymptotic expansion of the mean squared error (MSE) of the EBLUP. In particular, in the balanced case, i.e., when the sampling variances are equal, this best EBLUP has the minimal MSE in the exact sense. We also propose a modified Prasad–Rao MSE estimator which is second-order unbiased and show that it is less biased than the jackknife MSE estimator in a suitable sense in the balanced case. A real data example is discussed.

e15538Background: Gastric cancer is a heterogeneous disease. Whether the expression and amplification of c-Met/HER2 differ between the primary and metastatic lesion and their impacts on prognosis r...

Purpose: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. Aberrant hepatocyte growth factor / MET signaling has been implicated in hepatocarcinogenesis, suggesting that MET may serve as an attractive therapeutic target in HCC. The purpose of this study was to investigate the anti-tumor activity in vitro and in vivo of AMG 337, a potent and highly selective small molecule MET kinase inhibitor, in preclinical models of HCC. Experimental Design: The anti-proliferative activity of AMG 337 was evaluated across a panel of 40 HCC cell lines in a 72-hour viability assay. Daily oral administration of AMG 337 at doses of 3, 10 and 30 mg/kg was used to evaluate the in vivo anti-tumor activity of AMG 337 in two patient-derived mouse xenograft (PDX) models of HCC, LI0612 and LI1078. Effects on MET signaling were assessed by western blot analysis of downstream effector proteins including p-GAB1, p-AKT and p-ERK. MET protein levels and gene copy number for both PDX models and a subset of HCC cell lines were assessed by immunohistochemistry (IHC; Dako) and fluorescence in situ hybridization (FISH; Dako), respectively. High MET expression was defined as the presence of any tumor cells with membrane staining at 3+ intensity. MET amplification was defined as MET:CEN-7 ratio >2.0 or MET SNP array log2 copy number >2.5. Results: AMG 337 displayed potent anti-proliferative activity in two of 40 HCC cell lines (MHCC97H and HCCLM3) (IC50 0.015 μM and 0.025 μM, respectively); both cell lines were amplified for MET (MET/CEN-7 >2.0) and showed high MET expression (3+ IHC). AMG 337 potently inhibited p-MET in all cell lines with detectable levels of total MET. However, dose-dependent inhibition of p-GAB1, p-AKT and p-ERK was limited to those cell lines that were sensitive to AMG 337 in viability assays. AMG 337 significantly inhibited tumor growth at all doses tested (p < 0.001) in the MET-amplified and MET-high expressing HCC PDX model LI0612. However, AMG 337 had no effect on tumor growth in the non-MET-amplified and MET-low expressing HCC PDX model LI1078. Analysis of The Cancer Genome Atlas (TCGA) data identified four of 164 (2.4%) HCC tumor samples with MET amplification (https://tcga-data.nci.nih.gov/tcga), representing a patient population with potential to derive clinical benefit from AMG 337. Conclusions: These preclinical studies show that the efficacy of AMG 337 in HCC was highly associated with MET amplification. AMG 337 represents a promising, novel clinical therapeutic strategy for targeting HCC with a dependence on the MET pathway. Citation Format: Zhiqiang Du, Sean Caenepeel, Yuqing Shen, Karen Rex, Yanni Zhang, En-Tzu Tang, Ouhong Wang, Wenge Zhong, Hui Zhou, Jacqueline Huang, Eric Huang, Liaoyuan Hu, Angela Coxon, Mingqiang Zhang. Preclinical evaluation of AMG 337, a highly selective small molecule MET inhibitor, in hepatocellular carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5391. doi:10.1158/1538-7445.AM2015-5391

4048 Background: Gastric cancer is a disease with high unmet medical needs in China. MET and its ligand, hepatocyte growth factor, are potential targets in G/GEJ cancer. This study evaluated overal...

To determine the level of agreement among the Bone and Joint Decade Undergraduate Curriculum Group (BJDUCG) core curriculum recommendations for musculoskeletal (MSK) conditions targeted for undergraduate medical education and what the physicians and surgeons of Canada thought to be important at the postgraduate level of education.An 80-item questionnaire was developed. A cross-sectional survey of educators representing 77 Canadian accredited academic programs representing 6 disciplines in medicine that manage patients with MSK conditions was completed. Histograms, Kruskal-Wallis, and principal component analyses were computed.In total, 164/175 (94%) respondents participated in the study. All 80 curriculum items received a mean score of at least 3.0/4.0. Sixty-four out of 80 items were ranked to be at least 3.5/4.0, and 35 items were ranked to be at least 3.8/4.0, suggesting that these items may be core content for all disciplines.The World Health Organization declared the years 2000 to 2010 as The Bone and Joint Decade. The main goal is to improve the quality of life for people with MSK disorders worldwide. One aim of the BJD is to increase education of healthcare providers at all levels. The BJDUCG established a set of core curriculum recommendations for MSK conditions. Our study gives reliable statistical evidence of agreement among what the BJDUCG recommended for an MSK core curriculum for medical schools and what the physicians and surgeons of Canada thought to be important for residency education in several disciplines.

Summary The final analysis of this 2-year, randomized, crossover study showed that postmenopausal women with osteoporosis were more adherent, compliant, and persistent with subcutaneous denosumab injections every 6 months than with once-weekly alendronate tablets. After receiving both treatments, women reported greater satisfaction with injectable denosumab and preferred it over oral alendronate. Introduction Osteoporosis patients who are non-compliant or non-persistent with therapy may have suboptimal clinical outcomes. This 2-year, randomized, open-label, crossover study compared treatment adherence between subcutaneous denosumab, 60 mg every 6 months, and oral alendronate, 70 mg once weekly. Methods Postmenopausal women at 25 centers in the USA and Canada with bone mineral density T-scores −4.0 to −2.0 and no prior bisphosphonate use received alendronate then denosumab, or denosumab then alendronate, over successive 12-month periods. Adherence required both compliance (denosumab injections 6 months apart or ≥80% of alendronate tablets) and persistence (both denosumab injections or ≥2 alendronate doses in the last month and completion of the treatment period). Results Of the 250 women enrolled (124 alendronate, 126 denosumab), 221 entered the second year (106 denosumab, 115 alendronate). Denosumab was associated with less non-adherence than alendronate (first year, 11.9% vs 23.4%; second year, 7.5% vs 36.5%). Risk ratios for non-adherence, non-compliance, and non-persistence favored denosumab in both years (p