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Purpose A sensitive and specific imaging biomarker to monitor immune activation and quantify pharmacodynamic responses would be useful for development of immunomodulating anti-cancer agents. PF-07062119 is a T cell engaging bispecific antibody that binds to CD3 and guanylyl cyclase C, a protein that is over-expressed by colorectal cancers. Here, we used 89Zr-Df-IAB22M2C (89Zr-Df-Crefmirlimab), a human CD8-specific minibody to monitor CD8+ T cell infiltration into tumors by positron emission tomography. We investigated the ability of 89Zr-Df-IAB22M2C to track anti-tumor activity induced by PF-07062119 in a human CRC adoptive transfer mouse model (with injected activated/expanded human T cells), as well as the correlation of tumor radiotracer uptake with CD8+ immunohistochemical staining. Procedures NOD SCID gamma mice bearing human CRC LS1034 tumors were treated with four different doses of PF-07062119, or a non-targeted CD3 BsAb control, and imaged with 89Zr-Df-IAB22M2C PET at days 4 and 9. Following PET/CT imaging, mice were euthanized and dissected for ex vivo distribution analysis of 89Zr-Df-IAB22M2C in tissues on days 4 and 9, with additional data collected on day 6 (supplementary). Data were analyzed and reported as standard uptake value and %ID/g for in vivo imaging and ex vivo tissue distribution. In addition, tumor tissues were evaluated by immunohistochemistry for CD8+ T cells. Results The results demonstrated substantial mean uptake of 89Zr-Df-IAB22M2C (%ID/g) in PF-07062119-treated tumors, with significant increases in comparison to non-targeted BsAb-treated controls, as well as PF-07062119 dose-dependent responses over time of treatment. A moderate correlation was observed between tumor tissue radioactivity uptake and CD8+ cell density, demonstrating the value of the imaging agent for non-invasive assessment of intra-tumoral CD8+ T cells and the mechanism of action for PF-07062119. Conclusion Immune-imaging technologies for quantitative cellular measures would be a valuable biomarker in immunotherapeutic clinical development. We demonstrated a qualification of 89Zr-IAB22M2C PET to evaluate PD responses (mice) to a novel immunotherapeutic.

The advent of immuno-oncology (IO) therapies has made it an imperative to characterize intratumoral immune microenvironment in addition to oncogenic alterations through molecular profiling of the tumor. To elucidate the baseline profiles of tumor infiltrating leukocytes (TILs) in breast cancer (BC) in the context of molecular subtypes and oncogenic alterations, we performed whole-exome sequencing (WES) and RNA-Seq of an Asian BC cohort (SMC) consisting of 178 treatment naïve primary tumors. A subset of 120 tumors was further analyzed by H&E and IHC using a panel of 8 TIL markers (CD45, CD4, CD8, CD163, PD1, PD-L1, IDO1 and FOXP3). Using expression signatures representing distinct immune cell types, we classified an expression compendium of 2,781 tumor samples, including SMC and multiple cancers from TCGA, into three immune subtypes with high, medium and low levels of TILs. Basal and HER2 subtypes show higher levels of TILs than Luminal subtypes, consistent with observed clinical responses to checkpoint blockade in clinical trials. Moreover, Asian BCs were significantly enriched in TIL-high subtype (35.3%) compared to the primarily Caucasian TCGA BC cohort (20.2%) while 50.6% of the highly immunogenic Lung adenocarcinoma was TIL-high. We then applied machine learning methods to detect and quantify TILs from H&E images of 120 SMC and 349 TCGA BC tumors. The expression signature analysis results were concordant with independently derived histology based TIL data. Taken together, our findings suggest that IO therapies may be more effective in HR negative BC subtypes and Asian BCs. Leukocyte exclusion (LE), an immunophenotype where TILs concentrate at the tumor periphery, has been linked to worse prognosis and resistance to IO therapies. Visual assessment of whole tumor IHC images identified LE patterns in 25% of SMC cases. We observed differential distribution of LE by molecular subtype and evidence for selective exclusion of immune cell subsets. Covariate analyses with clinical and molecular data while controlling for subtype as a confounder identified significant associations with tumor proliferation index, percent tumor purity and TP53 mutations. LE is also significantly associated with expression signatures of chemokine signaling, macrophages, angiogenesis and hypoxia, indicating that marked distinctions exist in both tumor intrinsic and microenvironment characteristics between TIL excluded and TIL infiltrated tumors. To validate these findings, we independently identified LE for 200 cases of TCGA BCs based on patterns of TILs extracted from H&E images and saw significant concordance of covariate relationships identified between TCGA and SMC. Our study provided a rare comprehensive resource for studying tumor associated immunity in breast cancers by generating the integrated multi-omics and IO profiles for a large cohort of primary tumors. Comparative analyses revealed that TIL activities are highly variable across different intrinsic subtypes and geographic origins of BC, with potential implications for IO therapeutic application. Correlative analyses of immunophenotypes with molecular data further yielded insights into LE's role in immune escape and identified hallmark signatures for LE indicative of causal molecular mechanisms. Citation Format: Kan Z, Powell E, Ram S, Ching K, Ding Y, Vizcarra P, Nichols T, Hardwick J, Lee S-H, Cho SY, Choi Y-L, Yu J-H, Park YH. Integrative analyses of immunophenotypes and multi-omics profiles in breast cancers [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-07-01.

Purpose The ROS1 tyrosine kinase is activated through ROS1 gene rearrangements in 1% to 2% of non–small-cell lung cancers (NSCLCs), which confer sensitivity to treatment with the anaplastic lymphoma kinase (ALK)/ROS1/mesenchymal-epithelial transition factor inhibitor crizotinib. Currently, insights into patterns of metastatic spread and mechanisms of crizotinib resistance among patients with ROS1-positive disease are limited. Patients and Methods We reviewed clinical and radiographic imaging data of patients with ROS1- and ALK-positive NSCLC to compare patterns of metastatic spread at initial metastatic diagnosis. To determine molecular mechanisms of crizotinib resistance, we analyzed repeat biopsy specimens from a cohort of patients with ROS1-positive disease who progressed on crizotinib. Results We identified 39 and 196 patients with advanced ROS1- and ALK-positive NSCLC, respectively. Patients with ROS1-positive disease had significantly lower rates of extrathoracic metastases ( ROS1, 59.0%; ALK, 83.2%; P = .002), including lower rates of brain metastases ( ROS1, 19.4%; ALK, 39.1%; P = .033), at initial metastatic diagnosis. Despite similar overall survival between patients with ALK- and ROS1-positive NSCLC treated with crizotinib (median, 3.0 v 2.5 years, respectively; P = .786), patients with ROS1-positive NSCLC also had a significantly lower cumulative incidence of brain metastases (34% v 73% at 5 years; P < .001). In addition, we identified 16 patients who underwent a total of 17 repeat biopsies after progression on crizotinib. ROS1 resistance mutations were identified in 53% of specimens, including nine (64%) of 14 non–brain metastasis specimens. ROS1 mutations included G2032R (41%), D2033N (6%), and S1986F (6%). Conclusion Compared with ALK rearrangements, ROS1 rearrangements are associated with lower rates of extrathoracic metastases, including fewer brain metastases, at initial metastatic diagnosis. ROS1 resistance mutations, particularly G2032R, appear to be the predominant mechanism of resistance to crizotinib, which underscores the need to develop novel ROS1 inhibitors with activity against these resistant mutants.

Patient-Derived Xenograft (PDX) provides important preclinical model for pharmacological testing of oncology drug candidates. Molecular profiling of PDX tumors contributes to many areas of drug discovery from target discovery to development of clinical biomarker hypotheses and clinical trial design. We established a work flow to perform genomic and histopathology analyses of large numbers of PDX tumor models being made available for Pfizer internal research. To date we have generated whole-genome sequencing (WGS), whole-exome sequencing (WES) and whole transcriptome sequencing (RNA-Seq) data on PDX models spanning six cancer types including colon, pancreatic and breast cancers. Bioinformatics pipelines were developed to quantify gene expression and detect genetic alterations including mutation, copy number variations and gene fusions. A controlled evaluation study demonstrated that in silico classification of NGS reads into human/mouse origins is more effective than laboratory-based methods for removing mouse tissue contamination. Comparative analyses of molecular profiles from PDX and primary tumors of the same cancer origins suggest that important patterns of gene expression are retained by PDX models. An integrative genomic classifier was developed using the random forest algorithm, trained on primary tumor data, and shown to identify PDX cancer subtypes with high accuracy. Citation Format: Zhengyan Kan, Edward Rosfjord, James Hardwick, Ying Ding, Xianxian Zheng, Julio Fernandez, Stephanie Shi, Mark Ozeck, Hui Wang, Gabriel Troche, Eric Upeslacis, Amy Jackson-Fisher, Keith Ching, Shibing Deng, Xie Tao, John Chionis, Maruja Lira, Xiaorong Li, Konstantinos Tsaparikos, Patrick Lappin, Pamela Vizcarra, David Shields, Judy Lucas, Paul Rejto. Molecular profiling of patient-derived xenograft models across cancers. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A2-33.

Preclinical studies have shown that targeted combination therapy consisting of vorinostat and bortezomib has antitumor activity in multiple myeloma (MM). We examined this drug combination in advanced relapsing and/or refractory MM patients (n = 34). Although the maximum tolerated dose was not reached, the study found this combination regimen generally well tolerated and clinically active in relapsed and/or refractory MM patients.Development of targeted therapies for MM has improved response rates and increased patient survival, but ultimately the disease becomes refractory and progresses. Vorinostat combined with bortezomib has demonstrated synergistic antiproliferative and proapoptotic activity in preclinical models of MM. The objectives of this study were to determine the maximum tolerated dose for vorinostat with bortezomib in patients with advanced MM and to evaluate the clinical benefit of this new drug combination.Patients ≥ 18 years old with relapsed and/or refractory MM were enrolled into escalating dose cohorts of vorinostat and bortezomib combination therapy. Thirty-four patients were enrolled and were evaluable for safety and efficacy analyses.All patients reported adverse events, 89% of which were mild to moderate in severity. Thirteen patients experienced 29 serious adverse events, 12 (41%) of which were considered drug-related. The maximum tolerated dose was not reached. Partial responses were observed in 9 (27%) patients. Minimal responses were observed in 2 additional patients (6%), and another 20 patients (59%) experienced disease stabilization.Vorinostat with bortezomib is generally well-tolerated and has clinical activity in patients with relapsed and/or refractory MM. Response rates were similar in patients previously exposed to bortezomib and patients who were naive to bortezomib therapy.

The retinoid X receptor (RXR)-agonist bexarotene and the histone deacetylase inhibitor (HDACI) vorinostat are each established monotherapies for cutaneous T-cell lymphomas (CTCLs). We investigated the combination of HDACI and retinoic acid receptor (RAR)/RXR agonists in vitro and in a phase I, multicenter, open-label, two-part dose-escalation study. The combination of bexarotene with a HDACI in vitro leads to cooperative activation of gene transcription and reduction of cell viability in human tumor cell lines. The primary clinical objective was to determine the maximum tolerated dose (MTD) of bexarotene plus vorinostat in 23 patients with CTCLs. The MTD for part I was established at vorinostat 200 mg/day plus bexarotene 300 mg/m(2)/day. The MTD for part II was not reached. Four patients had an objective response and seven patients experienced pruritus relief. We conclude that concomitant administration of vorinostat and bexarotene is feasible only if lower doses of each drug are administered relative to the product label monotherapy doses.

Background: The Hedgehog (Hh) signaling pathway is key to development, differentiation, and stem cell maintenance. In cancer, dysregulation of Hh signaling is associated with solid tumors and hematological malignancies. Hh signaling in AML and MDS is thought to promote the renewal and maintenance of leukemic stem cells, which may lead to chemotherapy resistance and recurrence. Glasdegib is a potent and selective oral inhibitor of Smoothened, a transmembrane protein that stimulates Hh signaling. Here we report the results of an exploratory analysis to profile mutations in 118 bone marrow samples and 77 peripheral blood samples of patients with previously untreated AML or high-risk MDS treated with chemotherapy with or without glasdegib in phase I/II clinical trials. Materials and Methods: We used targeted resequencing to survey 109 genes, and a polymerase chain reaction assay to detect FLT3 internal tandem duplications. Resequencing and response data were obtained from two arms, 1) an intensive group (n=61) treated with a combination of cytarabine/daunorubicin plus glasdegib, and 2) a non-intensive group (n=73) treated with low-dose cytarabine (LDAC) plus glasdegib (n=44) or LDAC alone (n=19). We assessed significantly mutated genes by Fisher's Exact Test at p ≤ 0.05. Results: In the combined dataset we found that mutations in NF1 (P=0.006), KRAS (P=0.028), or a combination of KRAS, NRAS, and NF1 (P=0.013) were associated with a negative response. Mutations in NPM1 (P=0.006), MPL (P=0.041), RB1 (P=0.041), or SF3B1 (P=0.041) were associated with a positive response. When split by arm, in the intensive group mutations in TP53 (P=0.001), NF1 (P=0.035), or CREBBP (P=0.041) were associated with negative response, whereas mutation in NPM1 was associated with positive response (P=0.046). In the non-intensive group, mutations in RSPH10B2 (P=0.036) or a combination of KRAS, NRAS, and NF1 (P=0.031) were associated with negative response, whereas mutation in CREBBP (P=0.007) was associated with positive response. We discuss the implications of these mutations in the context of Smoothened inhibition and the leukemic stem cell hypothesis. Conclusions: Mutational profiling of patients with AML or high-risk MDS treated with glasdegib highlights alterations in genes associated with response and the potential role of Hh signaling in these malignancies. Citation Format: Keith A. Ching, Donghui Huang, Kai Wang, Mark Ozeck, Paul Lira, Jingjin Gao, Jadwiga Bienkowska, Paul Rejto, James Hardwick, Thomas O'Brien, Geoffrey Chan. Analysis of mutations associated with response to glasdegib in acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-215.

Antiangiogenic agents such as vascular endothelial growth factor receptor 2 (VEGFR2) inhibitors may prove most efficacious in the setting of early disease and in the prevention of dissemination and growth of micrometastases. This hypothesis was tested in a metastatic orthotopic rat model of breast cancer with the use of a novel orally bioavailable VEGFR2 kinase inhibitor, MK-0888. Mat B III rat mammary cancer cells were implanted into the mammary fat pads of syngeneic female F344 rats. Primary tumor growth was very aggressive, with micrometastases detected 8 days after cell implantation in ipsilateral axillary and inguinal lymph nodes. Lung metastases were detected 15 days after cell implantation by histological analysis. MK-0888 suppressed primary and metastatic tumor growth and reduced the incidence of metastasis in a dose- and schedule-dependent manner. Inhibitions of primary and metastatic tumor growth, as well as intratumoral antiangiogenesis effects, were detected in situ by immunohistochemi...

Gastric cancer, a leading cause of cancer-related deaths, is a heterogeneous disease. We aim to establish clinically relevant molecular subtypes that would encompass this heterogeneity and provide useful clinical information. We use gene expression data to describe four molecular subtypes linked to distinct patterns of molecular alterations, disease progression and prognosis. The mesenchymal-like type includes diffuse-subtype tumors with the worst prognosis, the tendency to occur at an earlier age and the highest recurrence frequency (63%) of the four subtypes. Microsatellite-unstable tumors are hyper-mutated intestinal-subtype tumors occurring in the antrum; these have the best overall prognosis and the lowest frequency of recurrence (22%) of the four subtypes. The tumor protein 53 (TP53)-active and TP53-inactive types include patients with intermediate prognosis and recurrence rates (with respect to the other two subtypes), with the TP53-active group showing better prognosis. We describe key molecular alterations in each of the four subtypes using targeted sequencing and genome-wide copy number microarrays. We validate these subtypes in independent cohorts in order to provide a consistent and unified framework for further clinical and preclinical translational research.

Liquid biopsies have the potential to revolutionize the way physicians select personalized anti-cancer therapies, monitor patient responses to treatment, and characterize acquired resistance to cancer drugs. New tests that use a simple peripheral blood draw offer snapshots of a patient‘s total tumor DNA mutation profile and are attractive because of their minimally-invasive modality and because they integrate information from both primary and metastatic disease. Currently, most plasma cell-free DNA (cfDNA) mutation detection tests used in clinical research detect known hotspot mutations in a limited number of genes. Technologies that interrogate multi-gene panels in cfDNA are advancing, but commercially-available options suitable for clinical use are limited, come at a high cost, and are not customizable. We designed and developed a customized, next generation sequencing-based, liquid biopsy assay capable of detecting somatic mutations in 87 breast cancer genes involved in cell cycle and estrogen receptor signaling. Targeted regions (147 Kb) were enriched using hybrid capture resulting in an average capture specificity and uniformity of 65.93% and 96.38%, respectively. When tested on cfDNA from healthy donors (n=14), we demonstrated a level of specificity >99.99%. Analytical sensitivity of 0.1% was established on HapMap and reference mutant cell line DNA. Using a pool of HapMap genomic DNA (n=10), 96% (48/50) of SNPs with expected allele frequency of 0.1% were detected. In reference mutant cell line DNA with 1% or 0.1% mutant allele frequencies, we were able to reliably detect all mutations present at 1% and mutations at 0.1% in 50% of the cases. Assay validation on plasma cfDNA with matching tumor from ER+, HER2- breast cancer patients will be presented. In conclusion, we developed a highly sensitive and specific liquid biopsy assay to interrogate 87 breast cancer-related genes. The high level of specificity and sensitivity makes the test ideal not only for detecting known cancer gene hotspot mutations but also for detection of novel gene mutations that may arise during treatment as a result of acquired drug resistance. Citation Format: Maruja E. Lira, Tao Xie, Shibing Deng, Jennifer Kinong, Jingjin Gao, Zhou Zhu, Nathan Lee, Paul Rejto, Jadwiga Bienkowska, James Hardwick, Kai Wang, Stephen Huang. Liquid biopsy testing allows highly-sensitive detection of plasma cfDNA mutations in 87 breast cancer-related genes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2749. doi:10.1158/1538-7445.AM2017-2749

Purpose: Insulin-like growth factor-1 receptor (IGF-1R) mediates cellular processes in cancer and has been proposed as a therapeutic target. Dalotuzumab (MK-0646) is a humanized IgG1 monoclonal antibody that binds to IGF-1R preventing receptor activation. This study was designed to evaluate the safety and tolerability of dalotuzumab, determine the pharmacokinetic (PK) and pharmacodynamic (PD) profiles, and identify a recommended phase II dose. Experimental Design: Patients with tumors expressing IGF-1R protein were allocated to dose-escalating cohorts of three or more patients each and received intravenous dalotuzumab weekly, every 2 or 3 weeks. Plasma was collected for PK analysis. Paired baseline and on-treatment skin and tumor biopsy samples were collected for PD analyses. Results: Eighty patients with chemotherapy-refractory solid tumors were enrolled. One dose-limiting toxicity was noted, but a maximum-tolerated dose was not identified. Grade 1 to 3 hyperglycemia, responsive to metformin, occurred in 15 (19%) patients. At dose levels or more than 5 mg/kg, dalotuzumab mean terminal half-life was 95 hours or more, mean Cmin was more than 25 μg/mL, clearance was constant, and serum exposures were approximately dose proportional. Decreases in tumor IGF-1R, downstream receptor signaling, and Ki67 expression were observed. 18F-Fluorodeoxy-glucose positron emission tomography metabolic responses occurred in three patients. One patient with Ewing's sarcoma showed a mixed radiologic response. The recommended phase II doses were 10, 20, and 30 mg/kg for the weekly, every other week, and every third week schedules, respectively. Conclusions: Dalotuzumab was generally well-tolerated, exhibited dose-proportional PK, inhibited IGF-1R pathway signaling and cell proliferation in treated tumors, and showed clinical activity. The low clearance rate and long terminal half-life support more extended dosing intervals. Clin Cancer Res; 17(19); 6304–12. ©2011 AACR.

Purpose Addition of aprepitant, a neurokinin-1 receptor antagonist (NK1RA), to an ondansetron and dexamethasone regimen improves prevention of chemotherapy-induced nausea/vomiting (CINV), particularly during the delayed phase (DP; 25 to 120 hours). Therefore, recommended antiemetic regimens include multiple-day NK1RA administration. Preliminary data suggested that single-dose aprepitant before chemotherapy could provide CINV protection throughout the overall risk phase (OP; 0 to 120 hours). This study compared a 3-day oral aprepitant schedule to a regimen containing a single dose of the intravenous NK1RA fosaprepitant. Patients and Methods A randomized, double-blind, active-control design was used to test whether fosaprepitant is noninferior to aprepitant. Patients receiving cisplatin ≥ 70 mg/m2 for the first time received ondansetron and dexamethasone with a standard aprepitant regimen (125 mg on day 1, 80 mg on day 2, 80 mg on day 3) or a single-dose fosaprepitant regimen (150 mg on day 1). The primary end point was complete response (CR; no vomiting, no rescue medication) during OP. Secondary end points were CR during DP and no vomiting during OP. Accrual of 1,113 evaluable patients per treatment arm was planned to confirm noninferiority with expected CR of 67.7% and noninferiority margin of minus 7 percentage points. Results A total of 2,322 patients were randomly assigned, and 2,247 were evaluable for efficacy. Antiemetic protection with aprepitant and fosaprepitant was equivalent within predefined bounds for noninferiority. Both regimens were well tolerated, although more frequent infusion site pain/erythema/thrombophlebitis was seen with fosaprepitant relative to aprepitant (2.7% v 0.3%, respectively). Conclusion Given with ondansetron and dexamethasone, single-dose intravenous fosaprepitant (150 mg) was noninferior to standard 3-day oral aprepitant in preventing CINV during OP and DP.

Vorinostat (suberoylanilide hydroxamic acid), a potent, oral histone deacetylase inhibitor, has demonstrated clinical activity in non-Japanese patients with various hematological and solid tumors. We sought to determine the maximum tolerated dose and a recommended phase II dose for 18 Japanese patients with solid tumors (median age, 58 years; range, 25-72 years) who failed standard therapy. Patients received vorinostat for 14 days followed by a 7-day rest. The initial dose was 100 mg twice daily escalating by 100 mg twice daily. Once-daily dosing was tested at 400 and 500 mg. A maximum tolerated dose could not be identified. Dose-limiting toxicities (thrombocytopenia, anorexia, and fatigue) were observed in two of six patients receiving 200 mg twice daily and in one of six patients receiving 500 mg once daily. In the 100-500 mg dose range, vorinostat area under the concentration-time curve increased in proportion to dose with a pharmacokinetic profile similar to that established in non-Japanese patients. Vorinostat doses of 200 mg twice daily or 500 mg once daily for 14 days followed by a 7-day rest were well tolerated and are candidate doses for phase II trials, although a maximum tolerated dose for vorinostat was not reached.

Aprepitant was shown previously to be effective for prevention of chemotherapy-induced nausea and vomiting (CINV) with moderately emetogenic chemotherapy (MEC) in breast cancer patients receiving an anthracycline and cyclophosphamide (AC)-based regimen. This study assessed aprepitant in patients receiving a broad range of MEC regimens with a variety of tumor types.This phase III, randomized, gender-stratified, double-blind trial enrolled patients with confirmed malignancies, naïve to MEC or highly emetogenic chemotherapy, who were scheduled to receive a single dose of at least one MEC agent. Patients received an aprepitant triple-therapy regimen (aprepitant, ondansetron, and dexamethasone) or a control regimen (ondansetron and dexamethasone) administered orally. Primary and key secondary efficacy endpoints were proportions of patients with no vomiting and complete response (no vomiting and no rescue medication), respectively, during the 120 h post-chemotherapy.Of 848 randomized patients, 77% were female, and 52% received non-AC-based antineoplastic regimens. Significantly, more patients in the aprepitant group achieved no vomiting and complete response, regardless of whether they received AC or non-AC regimens, in the 120 h after chemotherapy. Overall, the incidences of adverse events were generally similar in the aprepitant (62.8%) and control groups (67.2%).The aprepitant regimen provided superior efficacy in the treatment of CINV in a broad range of patients receiving MEC (non-AC or AC) in both no vomiting and complete response endpoints. Aprepitant was generally well tolerated. These results show the benefit of including aprepitant as part of the standard antiemetic regimen for cancer patients receiving MEC.

Purpose Vorinostat, a histone deacetylase inhibitor, represents a rational therapeutic target in glioblastoma multiforme (GBM). Patients and Methods Patients with recurrent GBM who had received one or fewer chemotherapy regimens for progressive disease were eligible. Vorinostat was administered at a dose of 200 mg orally twice a day for 14 days, followed by a 7-day rest period. Results A total of 66 patients were treated. Grade 3 or worse nonhematologic toxicity occurred in 26% of patients and consisted mainly of fatigue (17%), dehydration (6%), and hypernatremia (5%); grade 3 or worse hematologic toxicity occurred in 26% of patients and consisted mainly of thrombocytopenia (22%). Pharmacokinetic analysis showed lower vorinostat maximum concentration and area under the curve (0 to 24 hours) values in patients treated with enzyme-inducing anticonvulsants, although this did not reach statistical significance. The trial met the prospectively defined primary efficacy end point, with nine of the first 52 patients being progression-free at 6 months. Median overall survival from study entry was 5.7 months (range, 0.7 to 28+ months). Immunohistochemical analysis performed in paired baseline and post-vorinostat treatment samples in a separate surgical subgroup of five patients with recurrent GBM showed post treatment increase in acetylation of histones H2B and H4 (four of five patients) and of histone H3 (three of five patients). Microarray RNA analysis in the same samples showed changes in genes regulated by vorinostat, such as upregulation of E-cadherin (P = .02). Conclusion Vorinostat monotherapy is well tolerated in patients with recurrent GBM and has modest single-agent activity. Histone acetylation analysis and RNA expression profiling indicate that vorinostat in this dose and schedule affects target pathways in GBM. Additional testing of vorinostat in combination regimens is warranted.

Vorinostat (suberoylanilide hydroxamic acid, SAHA) is a histone deacetylase inhibitor active clinically in cutaneous T-cell lymphoma and preclinically in leukemia. A phase 1 study was conducted to evaluate the safety and activity of oral vorinostat 100 to 300 mg twice or thrice daily for 14 days followed by 1-week rest. Patients with relapsed or refractory leukemias or myelodysplastic syndromes (MDS) and untreated patients who were not candidates for chemotherapy were eligible. Of 41 patients, 31 had acute myeloid leukemia (AML), 4 chronic lymphocytic leukemia, 3 MDS, 2 acute lymphoblastic leukemia, and 1 chronic myelocytic leukemia. The maximum tolerated dose (MTD) was 200 mg twice daily or 250 mg thrice daily. Dose-limiting toxicities were fatigue, nausea, vomiting, and diarrhea. Common drug-related adverse experiences were diarrhea, nausea, fatigue, and anorexia and were mild/moderate in severity. Grade 3/4 drug–related adverse experiences included fatigue (27%), thrombocytopenia (12%), and diarrhea (10%). There were no drug-related deaths; 7 patients had hematologic improvement response, including 2 complete responses and 2 complete responses with incomplete blood count recovery (all with AML treated at/below MTD). Increased histone acetylation was observed at all doses. Antioxidant gene expression may confer vorinostat resistance. Further evaluation of vorinostat in AML/MDS is warranted.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, with a 5 year survival rate of less than 5%. Deaths caused by pancreatic cancer are projected to exceed the number from colorectal carcinoma by 2020, making PDAC the second leading cause of cancer-related death in the United States, behind only NSCLC. At the molecular level, PDAC is enriched for a number of genetic events central to CDK4/6:CyclinD1 control of cell cycle progression - 90% of tumors harbor oncogenic KRAS mutations, which are synthetic lethal with CDK4/6 inhibition, while the majority of PDAC cases also feature loss of p16INK4A, the endogenous inhibitor of CDK4/6. Rb loss is uncommon in PDAC and phosphorylation of Rb, the canonical CDK4/6 substrate, is detectable at high frequencies, suggesting that aberrant CDK4/6 signaling may be central to loss of cell cycle control in pancreatic cancer. To determine the significance of CDK4/6 activity in pancreatic cancer, patient-derived xenograft models of early and late stage disease were used to evaluate the selective CDK4/6 inhibitor, palbociclib. Combinatorial efficacy of palbociclib with the standard of care agents, Gemcitabine and nab-paclitaxel (Gem/nab-Pac) was also assessed. The majority of models display greater than 50% tumor growth inhibition following treatment with single agent palbociclib, which is comparable to the response to Gem/nab-Pac in those models. Addition of palbociclib to Gem/nab-Pac confers further benefit in most models by increasing the degree of tumor response on therapy and/or maintaining tumor response after drug removal. To dissect the driver activities in the triplet combination, palbociclib was assessed in combination with either Gem or nab-Pac in a series of tumor growth inhibition/delay studies. Palbociclib and nab-Pac are the dominant agents in the combination - palbociclib/nab-Pac doublet activity surpasses the anti-tumor effects of Gem/nab-Pac in the majority of models, while palbociclib/nab-Pac is equivalent or superior to the triple combination in all models. In contrast, the addition of palbociclib to Gem yields little signs of positive combinatorial activity. Based on these data, the palbociclib/nab-Pac combination will be evaluated in an upcoming clinical trial for PDAC patients. Ongoing pre-clinical studies are focused on the mechanistic and molecular basis for the robust activity of the palbociclib/nab-Pac combination in pancreatic cancer. Citation Format: Manuel Hidalgo, Camino Menendez, Jing Yuan, Beatriz Salvador, Tao Xie, John Chionis, Pedro Lopez-Casas, Xianxian Zheng, James Hardwick, Paul Rejto, Peter Olson, Todd VanArsdale, David J. Shields. Palbociclib potentiates nab-paclitaxel efficacy in pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A42.

Lung cancer remains one of the leading causes of cancer-related mortality. Squamous cell lung cancer (SqCLC) is the second most common subtype of non-small cell lung cancer (NSCLC). Despite recent development of effective targeted therapeutic agents for lung adenocarcinoma, patients with SqCLC often receive conventional cytotoxic chemotherapy as this cancer subtype lacks genomic alterations that can be targeted by personalized medicine. Hence, novel approaches that enhance the efficacy of chemotherapy will benefit treatment outcomes in this patient population. CDK inhibitors comprise a class of drugs that targets the dysregulated cell cycle in malignant cells. Treatment of tumor cells with the CDK4/6 inhibitor palbociclib inhibits tumor growth by decreasing retinoblastoma (RB) protein phosphorylation and inducing cell cycle arrest at the G1/S phase transition. Based on promising clinical trial data, palbociclib in combination with letrozole was granted accelerated approval by the US FDA for the treatment of postmenopausal women with ER-positive, HER2-negative advanced breast cancer. In this preclinical study, we explored the effect of palbociclib on several chemotherapies (taxanes, platins, and antimetabolites) in preclinical models of SqCLC. Because the activity of chemotherapy generally requires cell cycle progression, careful combination/sequencing of this class of drugs with CDK inhibitors may be important to achieve synergy as well as avoid potential antagonism. To obtain optimal activity of palbociclib and chemotherapy combinations, we investigated several combination/sequencing regimens (concurrent, chemotherapy followed by palbociclib or the reverse sequence) in several SqCLC cell lines. We did not encounter antagonism of chemotherapy-mediated cytotoxicity by palbociclib in any of the tested regimens. Rather, we observed robust combinatorial anti-cancer cell activity in all settings. Combination of palbociclib with chemotherapy was associated with reduction of RB phosphorylation and FOXM1 protein levels, and the induction of p21. Our studies demonstrated that, while palbociclib partially antagonized chemotherapy-induced apoptosis, it significantly synergized with chemotherapy to induce cell cycle arrest as well as a senescence-like phenotype. Cells pretreated with palbociclib plus cisplatin or palbociclib plus docetaxel displayed less cell growth upon drug removal compared to those treated with monotherapies. Finally, palbociclib treatment that followed docetaxel, nab-paclitaxel or cisplatin treatment significantly enhanced the antitumor activity of the chemotherapies in several cell line-derived or patient-derived xenograft models. Our results suggest that treatment with optimal palbociclib and chemotherapy combination/sequencing could lead to better clinical outcomes for SqCLC patients. Citation Format: Ping Wei, Joan Cao, Goldie Lui, Hui Wang, Konstantinos Tsaparikos, David Shields, Kim Arndt, Paul Rejto, Todd VanArsdale, James Hardwick. RB pathway disruption by the CDK4/6 inhibitor palbociclib enhances responses to chemotherapy in squamous cell lung cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A43.

Clinical development of cancer therapies is associated with attrition rates as high as 80-95%. This high attrition suggests that standard preclinical pharmacology models do not accurately reflect clinical responses. The development of more predictive preclinical models requires several considerations; the relevance of the in vivo model, the administration of test agent, and the interpretation of efficacy data. PDX are cancer models developed from the direct transfer of patient tumor tissue into immunocompromised mice. A collection of PDX models, by retaining the genetic and histologic characteristics of the patients from which they were derived, represents the complexity and heterogeneity of human cancer. To minimize the clinical attrition rates of oncology compounds, we are developing hundreds of PDX models in seven major cancer indications. The collection is being molecularly profiled by RNAseq, WES, and proteomics. Profiling has identified models with robust expression of target proteins or mutant oncogenes that are likely to respond in preclinical efficacy tests. Conversely, the PDX models may provide an understanding of resistance, for example evaluating models with good target expression that fail to respond to therapy. Patient and tumor information, if known, has been collected for each PDX model including age, sex, cancer stage and grade, diagnosis, primary or metastatic site, and prior treatments. In addition to the improvements provided by the PDX models, a preclinical paradigm shift away from treatment with maximally tolerated dose towards clinically relevant dose (CRD), taking into consideration such aspects as exposure, formulation, route and schedule, is critical when attempting to predict clinical outcome from preclinical data. Also essential is the incorporation of clinically meaningful endpoints (regression) when assessing preclinical activity. We have initiated studies on cohorts of non small cell lung and breast PDX models to predict the likely clinical efficacy of candidate compounds for clinical development and to determine the CRD for standard of care (SOC) regimens required to define the most promising Phase II/III combination therapies. Anti-tumor activities were characterized using RECIST criteria of progressive disease (PD), stable disease (SD), partial response (PR), and complete response (CR). Target expression was evaluated by RNA, proteomics and immunohistochemistry. Preliminary results demonstrate a spectrum of responses against experimental therapeutics, including Phase I ADCs and are defining the CRD required for combination treatments with SOC. Identification of the most critical parameters of PDX models predicting clinical outcome will help in validating the utility of ‘n of 1′ studies with the PDX collection, inform patient enrollment strategies, guide combination therapies, and provide insight for identifying new tumor indications. Citation Format: Edward Rosfjord, Xin Han, Danielle Leahy, Erik Upeslacis, Justin Lucas, Jonathon Golas, Andrea Hooper, Fred Immermann, Bingwen Lu, Jeremy Myers, Zhengyan Kan, James Hardwick, Eric Powell, Puja Sapra, Paul Rejto, Hans-Peter Gerber, Judy Lucas. Patient derived xenograft (PDX) models: improving predictability of experimental cancer therapies. [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 1469. doi:10.1158/1538-7445.AM2015-1469

Crizotinib (PF-02341066) is a small molecule tyrosine kinase inhibitor of ALK, ROS1 and c-MET that is approved in over 70 countries for the treatment of ALK fusion positive non-small cell lung cancer (ALK+ NSCLC). Crizotinib achieved robust objective response rates of approximately 60% in ALK+ NSCLC and significantly improved progression free survival compared to chemotherapy. The emergence of secondary mutations within the ALK kinase domain or the activation of compensatory signaling pathways in crizotinib and other ALKi refractory tumors prompted searches for next generation of ALKi active against resistance mutations as single agents or in combination with other treatments. Such effort led to our recent discovery of PF-06463922, an ALK/ROS1 inhibitor with greatly improved ALK potency, brain penetration, and broad spectrum activity against all known clinical ALKi-resistant mutations. PF-06463922 is being tested in a Phase I clinical trial in both ALK+ and ROS1 fusion positive NSCLC in treatment naive or ALKi relapsed patients. In our current preclinical study, we explored rational combination strategies to further improve the efficacy of PF-06463922 in ALKi resistant cells or tumors. Our results show that compared to PF-06463922 alone, the combination of this compound with PI3K pathway inhibitors, such as PF-05212384 (PI3K/mTOR), GDC0941 (pan-PI3K) or GDC0032 (beta-sparing) leads to more robust anti-proliferative activity in vitro and greater duration of efficacy in vivo in the ALKi resistant models. These PI3K pathway inhibitors also partially overcome EGF or HGF ligand-induced resistance to PF-06463922. Interestingly, in addition to AKT signaling, both compounds inhibit ERK signaling as well, which may be essential for their enhancement of PF-06463922 cell activity or tumor efficacy in combination settings. Studies are ongoing to identify optimal partners for PF-06463922 combination using isoform selective PI3Ki, AKTi and mTORi. We are also exploring the breadth of efficacy of this combination in overcoming resistance to crizotinib, PF-06463922 or other ALKi. The findings provide important evidence that will help define the clinical development path for PF-06463922. This research effort may ultimately lead to more effective approaches to treat ALKi refractory patients in the clinic. Citation Format: Ping Wei, Ming Qiu, Nathan Lee, Joan Cao, Hui Wang, Konstantinos Tsaparikos, Conglin Fan, Timothy Sargis, Justine Lam, Maruja E. Lira, Goldie Lui, James Hardwick, Valeria Fantin, Paul Rejto, Tod Smeal. Rational combination of PF-06463922 (next-generation ALK inhibitor) with PI3K pathway inhibitors overcomes ALKi resistance in EML4-ALK+ NSCLC models. [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 764. doi:10.1158/1538-7445.AM2015-764

Hepatocellular carcinoma (HCC) is one of the most deadly cancers worldwide and has no effective treatment, yet the molecular basis of hepatocarcinogenesis remains largely unknown. Here we report findings from a whole genome sequencing (WGS) study of 88 matched HCC tumour/normal pairs, 81 of which are HBV positive, seeking to identify genetically altered genes and pathways implicated in HBV-associated HCC. We find β-catenin to be the most frequently mutated oncogene (15.9%) and TP53 the most frequently mutated tumour suppressor (35.2%). The Wnt/β-catenin pathway, altered in 62.5% of cases, is likely to act as the major oncogenic driver in HCC. TP53 alterations appear to cause increased levels of genomic arrangement and chromosomal instability. We identified chromothripsis in 5 HCC genomes (5.7%) recurrently affecting chromosomal arms 1q and 8q. We also identified recurrent HBV integration events at the known and putative cancer-related genes such as TERT, MLL4 and CCNE1, which showed upregulated gene expression in tumour versus normal tissue. The frequently altered genes and pathways in HCC reflect classical cancer hallmarks. This study identified several prevalent and actionable mutations that provide a path towards therapeutic intervention of the disease. Citation Format: Mao Mao, Hancheng Zheng, Zhengyan Kan, Jiangchun Xu, Xiao Liu, Shuyu Li, Thomas Barber, Zhuolin Gong, Huan Gao, Ke Hao, Melinda Willard, Robert Hauptschein, Paul Rejto, Julio Fernandez, Guan Wang, Qinghui Zhang, Bo Wang, Ronghua Chen, Jian Wang, Nikki Lee, Wei Zhou, Zhao Lin, Zhiyu Peng, Kang Yi, Shengpei Chen, Lin Li, Xiaomei Fan, Jie Yang, Rui Ye, Jia Ju, Kai Wang, Heather Estrella, Shibing Deng, Ping Wei, Ming Qiu, Isabella Wulur, Jiangang Liu, Mariam Ehsani, Chunsheng Zhang, Andrey Loboda, Wing Kin Sung, Amit Aggarwal, Ronnie Poon, Sheung Tat Fan, Jun Wang, James Hardwick, Christoph Reinhard, Hongyue Dai, Yingrui Li, John Luk. Whole genome sequencing reveals genetic landscape of hepatocellular carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-229. doi:10.1158/1538-7445.AM2013-LB-229

345 Background: It is well known that KRAS mutations limit the efficacy of anti-EGFR therapy in patients with mCRC. Therefore, accurate testing of KRAS is needed to ensure that appropriate patients receive anti-EFGR therapy. Most clinical institutions conduct KRAS testing in CLIA approved labs using standard DNA sequencing methods. The purpose of this study is to correlate KRAS mutation detection by Illumina KRAS gene sequencing to standard KRAS testing performed with CLIA. Methods: We analyzed tumor samples collected from 471 patients between 1998-2010. Patients were chosen randomly based on availability of sufficient tissue for DNA extraction. We performed targeted exome sequencing using an Illumina NGS platform with 50-100X coverage of KRAS. The BWA/GATK pipeline was used to identify variants and indels. Because matched normal samples were not available for comparison to identify somatic mutations, filtering of normal variants was performed using 1000 Genomes. Variants identified in 1000 Genomes with an MAF < 0.01 were filtered. Results: Out of 471 patients, 83 pts had KRAS testing done both by exome sequencing & CLIA approved labs. The concordance rate between the two testing methods was 89%. 39 pts (47%) were KRAS mutation negative (wild type) and 35 pts (46%) harbored KRAS mutation as determined by both methods. Of these, 31 pts had codon 12 mutations and 4 pts had codon 13 mutations. However, 6 pts (7%) were found to have no KRAS mutation using CLIA but were found to have KRAS mutations by NGS (two had A146V mutations, the others had Q61 mutations). In addition, 3 pts (4%) were KRAS mutants using CLIA but wild type by NGS. Thus, 10% of samples tested showed a discrepancy in outcome between the NGS & CLIA testing. Conclusions: Standard DNA sequencing methods (CLIA) was able to identify a majority of the KRAS mutants detected by NGS. However 10% of patients had either false positive or false negative results. The main explanation for this discrepancy is that CLIA approved labs generally only test for codons 12 & 13. The clinical role for NGS in tumor KRAS mutation detection should be further investigated to ensure that patients with mCRC receive appropriate therapy.

There is a large effort in the public domain to systematically perform DNA and RNA sequencing on large numbers of tumor samples. These efforts will bring us to a greater understanding of tumor biology and lead to identification of new tumor drivers. However, these efforts may fall short in allowing us to understand the progression of tumor resistance, relapse and metastasis, factors which make tumors difficult to treat and increase mortality rates. We are currently performing targeted DNA sequencing on 4000 tumor samples. We have selected 1321 genes, 5 GB of the genome to sequence. Genes were selected through a thorough review of the literature, mutation databases and key pathways in tumorigenesis such as growth factor signaling, DNA damage, p53 signaling, cell cycle and apoptosis. Our effort not only includes a diverse panel of breast, colon, ovarian, and kidney tumors but we have also sequenced pancreatic, liver, esophageal, cervix, endometrial, melanoma, CLL, DLBCL and carcinoid tumors. Our dataset also includes approximately 300 matched tumor-metastatic pairs and an additional 550 metastatic samples. Clinical phenotypes, treatment information, gene expression profiling and copy number variation data is available for all samples. To achieve the next level of care for cancer patients we must understand the biology of the tumors we are trying to treat, which are often metastatic and standard of care resistant. We believe that increasing our efforts in targeted DNA sequencing of key tumor and metastatic samples will allow us to achieve these goals. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 435. doi:1538-7445.AM2012-435

9021^ Background: Addition of a neurokinin-1 antagonist (NK1A) to a standard ondansetron (O) and dexamethasone (D) antiemetic regimen improves prevention of cisplatin-induced nausea/vomiting (CINV)...

Introduction The incidence of oesophageal and junctional adenocarcinoma has increased sixfold in the last 30 years and 5-year survival remains Methods Gene expression profiling was performed and the resulting 42 000 gene signatures correlated with clinical features for 91 snap frozen oesophageal and junctional resection specimens. External validation of selected targets was carried out on 371 independent cases using immunohistochemistry to maximise clinical applicability. Results Gene expression profiles were obtained from 75/91 of the samples (82%). 119 genes were significantly associated with survival and 270 genes with the number of involved lymph nodes. Ten of these genes were taken forward to external validation at the protein level. Three genes were prognostic in the external validation data set (TRIM44, SIRT2 and PAPSS2). Patients with dysregulation of none of these three genes had a significantly better outcome (5-year survival 48%) than those with dysregulation of one gene (5-year survival 29%), who in turn did better than those with two or more genes dysregulated (5-year survival 15%) (p=0.004). The three gene signature was independently prognostic in a multivariable model together with the existing clinical TNM staging system (p=0.003). Conclusion We have generated and externally validated an immunohistochemical prognostic gene signature which is independently highly prognostic in an external validation data set. In addition these three genes are possible therapeutic targets raising the possibility of personalised therapy based on a patient9s molecular prognostic signature. Our three gene signature is suitable for application in routine clinical practice and this study may provide a framework for similar future projects.

Purpose: Aprepitant was shown previously to be effective for prevention of CINV associated with MEC in breast cancer patients. A recent study (PN130) assessed aprepitant in patients with a variety of tumor types receiving a broad range of MEC regimens. A post-hoc subgroup analysis of patients with breast cancer was performed and results (nominal p-values) are reported.Methods: This randomized, gender-stratified, double-blind trial enrolled patients with confirmed malignancies, naïve to HEC or MEC agents, who received at least one MEC agent. Patients received an aprepitant triple-therapy regimen (aprepitant 125 mg PO day 1 and 80 mg PO days 2-3, ondansetron 8 mg PO bid day 1, and dexamethasone 12 mg PO day 1) or an active control regimen (ondansetron 8 mg PO bid days 1-3 and dexamethasone 20 mg PO day 1). Primary and key secondary efficacy endpoints were proportions of patients with No Vomiting and Complete Response (no vomiting/no rescue medication use) respectively, during the overall phase (120 hours post-chemotherapy). Treatment group comparisons were based on a logistic regression model with terms for treatment, region, and gender.Results: Of 832 patients in the modified intent to treat population analyzed, 53% (n=439) had breast cancer. In the overall phase, significantly more patients in the aprepitant group achieved No Vomiting and Complete Response both overall and in the subgroup of patients with breast cancer (Table 1). The magnitude of the treatment group differences were similar to the differences observed in the entire study population. Similar trends were seen in the acute and delayed phase in both the overall population and the subgroup of patients with breast cancer. Results for additional endpoints are consistent with the data presented here. Adverse events were generally similar in the aprepitant and control groups. Aprepitant, n/m (%)Active control, n/m (%)No vomitingAll tumors324/425 (76.2)*252/406 (62.1) Breast cancer152/219 (69.4)*116/220 (52.7)Complete responseAll tumors292/425 (68.7)*229/407 (56.3) Breast cancer139/219 (63.5)*102/220 (46.4)n/m = patients with favorable response/patients included in subgroup; * p-value < 0.001Conclusions: The aprepitant regimen provided superior efficacy over the control regimen for prevention of CINV for all patients receiving MEC. The benefit of aprepitant triple therapy in patients with breast cancer in this trial is in agreement with the results of a previous large-scale trial of aprepitant in this population. Control of CINV in breast cancer patients in this trial was consistently lower than in the overall population for all endpoints, demonstrating the importance of CINV prophylaxis in women with breast cancer undergoing MEC. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1116.

Abstract 1710 Poster Board I-736 Introduction Treatment regimens for cancer are typically based on cytotoxic chemotherapy, which is poorly tolerated. There is an unmet medical need for new therapies that retain efficacy, but combine this with an improved safety and tolerability profile. Vorinostat is a histone deacetylase (HDAC) inhibitor, approved in the United States for the treatment of cutaneous manifestations of cutaneous T-cell lymphoma (CTCL) in patients who have progressive, persistent, or recurrent disease on or following 2 systemic therapies. Vorinostat is also being investigated as a treatment for various other solid and hematologic malignancies, in which HDACs are further implicated as key regulators of transcription. Herein we present an overview of the safety and tolerability profile of vorinostat, gathered from prior clinical experience. Methods Safety and tolerability data, including adverse events (AEs), QTc interval data and incidence of thromboembolic events (TEE), were collated from patients who received vorinostat, administered as monotherapy or in combination therapy for solid or hematologic malignancies. Results (adverse events) In Phase I and II clinical trials, 498 patients who received vorinostat were analyzed. A total of 341 patients received vorinostat monotherapy (107 with CTCL, 105 other hematologic malignancies, 129 solid tumors) and the most common drug-related AEs in this group were: fatigue (61.9%), nausea (55.7%), diarrhea (49.3%), anorexia (48.1%), and vomiting (32.8%); Grade 3/4 AEs included fatigue (12.0%) and thrombocytopenia (10.6%), and 3 drug-related deaths (ischemic stroke, tumor hemorrhage, unspecified) occurred. Thirty-eight patients (11.1%) discontinued due to drug-related AEs, 71 patients (20.8%) required dose modifications, and 1 patient (0.3%) discontinued due to Grade 2 chest pain. The remaining 157 patients received vorinostat combination therapy (with pemetrexed/cisplatin for advanced cancer [n=46], bortezomib for multiple myeloma [n=34], bexarotene for CTCL [n=23], and erlotinib [n=30], gemcitabine/platin [n=21] or carboplatin/paclitaxel [n=3] for non-small-cell lung cancer). The most common drug-related AEs in this group were: nausea (48.4%), diarrhea (40.8%), fatigue (34.4%), and vomiting (31.2%); the most common Grade 3/4 AE was fatigue (13.4%), and 1 drug-related death (hemoptysis) occurred. Thirty-one patients (19.7%) discontinued due to drug-related AEs and 27 patients (17.2%) required dose modifications. Results (QTcF interval) A trial of 24 patients with advanced cancer was undertaken for rigorous assessment of QTcF interval. In this trial, a single supratherapeutic 800 mg dose of vorinostat did not prolong QTcF interval (monitored over 24 hours). The upper limit of the 90% confidence interval for the placebo-adjusted mean change-from-baseline of vorinostat was 30 msec, and 1 patient had a QTcF interval >450 msec (after both vorinostat and placebo administration). The most common drug-related AE in this trial was nausea. There were no serious clinical or laboratory AEs, no discontinuations due to an AE and no patients experienced a cardiac-related AE. Results (incidence of TEE) A review of vorinostat clinical trials, published literature and post-marketing surveillance reports was conducted by a committee of independent academic experts to determine the incidence of TEE in cancer patients who had received vorinostat. In >1845 patients reviewed through November 3, 2008, 107 patients ( Conclusions In this review, the majority of observed AEs were 'Grade 2, there was no observed prolongation of the QTcF interval, and the incidence of TEE with vorinostat was similar to reported rates of TEE in advanced cancer patients. Vorinostat is generally well tolerated when administered as monotherapy or in a combination regimen in cancer patients. Disclosures Siegel: Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celegne: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Rubin:Merck: Employment, Equity Ownership. Iwamoto:Merck: Employment, Equity Ownership. Hussein:Celgene: Employment. Belani:Merck: Consultancy. Hardwick:Merck: Employment, Equity Ownership. Rizvi:Merck: Employment, Equity Ownership.

2004 Background: Vorinostat is a histone deacetylase inhibitor that represents a rational therapeutic target in GBM. Methods: Recurrent GBM patients (pts) having received = 1 prior chemo regimen for progressive disease were eligible. Vorinostat dose was 200 mg bid x 14 days q 3 weeks. We applied a phase II design which had 90% power to declare the regimen active if the study PFS6 rate was 25%, a 15% rate increase over PFS6 in historical controls (10%). Results: 68 patients were treated. Grade 3+ non-hematologic toxicity consisting mainly of fatigue, diarrhea and dehydration occurred in 23% of pts; Grade 3+ hematologic toxicity consisting mainly of thrombocytopenia occurred in 25% of pts. Intra-patient dose escalation to 300 mg bid resulted in higher incidence of grade 3+ thrombocytopenia (45%) and was aborted. Pts receiving enzyme-inducing anticonvulsants (EIAC) had significantly less grade 3 + non-hematologic toxicity (p=0.01) and grade 3/4 thrombocytopenia (p=0.04). Pharmacokinetic analysis showed lower vorninostat C-max and AUC (0–24h) values and higher vorinostat-glucuronide C-max and AUC (0–24h) values in EIAC pts, although this did not reach statistical significance. The trial met the prospectively defined primary efficacy endpoint at the planned interim analysis with 5 of the first 22 patients (23%) being progression-free at 6 mo. RNA array analysis, performed in paired baseline and post-vorinostat treatment samples in a separate subgroup of 5 surgical recurrent GBM pts, who received vorinostat for 6 doses prior to surgery, showed upregulation of E-cadherin (p=0.02), thus indicating a biologic effect of the HDAC inhibitor on the glioblastoma tumors. Histone acetylation, Akt, phospho-Akt, P21Waf1/Cip1 and P27Kip1 expression analysis in all patients and correlation with outcome is ongoing. Conclusions: Vorinostat is well tolerated in recurrent GBM patients. EIAC patients have less toxicity, likely due to increased vorinostat metabolism via glucuronidation. Interim efficacy analysis is indicative of antitumor activity. Final efficacy analysis, RNA array data and correlative tissue analysis will be reported. No significant financial relationships to disclose.

Introduction The incidence rate of lung adenocarcinoma (LUAD), the predominant histological subtype of lung cancer, is elevated in Asians, particularly in female nonsmokers. The mutation patterns in LUAD in Asians might be distinct from those in LUAD in whites. Methods We profiled 271 resected LUAD tumors (mainly stage I) to characterize the genomic landscape of LUAD in Asians with a focus on female nonsmokers. Results Mutations in EGFR , KRAS , erb-b2 receptor tyrosine kinase 2 gene ( ERBB2 ), and BRAF ; gene fusions involving anaplastic lymphoma receptor tyrosine kinase gene ( ALK ), ROS1, and ret proto-oncogene ( RET ); and Met Proto-Oncogene Tyrosine Kinase ( MET ) exon 14 skipping were the major drivers in LUAD in Asians, exhibiting mutually exclusive and differing prevalence from those reported in studies of LUAD in non-Asians. In addition, we identified a novel mutational signature of XNX (the mutated base N in the middle flanked by two identical bases at the 5′ and 3′ positions) that was overrepresented in LUAD tumors in nonsmokers and negatively correlated with the overall mutational frequency. Conclusions In this cohort, approximately 85% of individuals have known driver mutations ( EGFR 59.4%, KRAS 7.4%, ALK 7.4%, ERBB2 2.6%, ROS1 2.2%, RET 2.2%, MET 1.8%, BRAF 1.1%, and NRAS 0.4%). Seventy percent of smokers and 90% of nonsmokers had defined oncogenic drivers matching the U.S. Food and Drug Administration–approved targeted therapies.