bluuebunny/crossref_metadata_2025 huggingface dataset:
Effectiveness of ASCO’s adverse event reporting decision aid: Results from an interventional study.
Authors: Mileham Kathryn Finch , Buchmeier Andrea D. , Chuk Meredith Kathleen , Davis Courtney , Forest Anne Marie , Garrett-Mayer Elizabeth , Hurley Patricia A. , Levit Laura , Perez Raymond P. , Schenkel Caroline , Vose Julie
Published: May 2019

3065

Background: Investigators often send adverse event (AE) reports to sponsors that are incorrectly categorized as serious or attributed to the investigational drug. Such errors contribute to a high volume of uninformative IND safety reports that sponsors submit to FDA and all participating investigators, straining stakeholder resources and impeding the detection of valid safety signals. To improve the quality of AE reporting, ASCO developed and tested a Decision Aid Tool (DAT). Methods: An interventional study with a cross-over design was conducted. Physician investigators and research staff were randomized to receive case studies. Cases were assessed for seriousness and attribution, first unassisted and then with the DAT. Participants completed a feedback survey. Effectiveness of reporting and attribution were assessed using logistic regression. Results are reported as odds ratios (OR) with 95% confidence intervals (CI). Results: Most of the 29 participants reported that the DAT was helpful (93%), improved their decision-making time (69%) and confidence in reporting (83%), and that they would use it in practice (83%). The DAT did not significantly affect accuracy of determining seriousness (OR, 0.87; 95% CI: 0.31, 2.46) but it did significantly increase accuracy of attributing a serious AE to a drug (OR, 3.60; 95% CI: 1.15, 11.4). Conclusions: The DAT shows promise as a method to reduce errors in attribution of AEs, which may help to ensure the detection of valid safety signals. Many participants were experienced clinical trialists, and the DAT may show greater utility as an educational tool for novice investigators, research staff, and students.
Image-guided surgery for tumor agnostic detection of solid tumors using the pH-activated micellar imaging agent ONM-100.
Authors: Voskuil Floris Jan , Steinkamp Pieter Jan , Koller Marjory , van der Vegt Bert , Doff Jan Johannes , Zhao Tian , Hartung Jeffrey P. , Jayalakshmi Yalia , Sumer Baran D. , Gao Jinming , Witjes Max J.H. , Van Dam Gooitzen Michell
Published: May 2019

3068

Background: ONM-100, a micelle-based polymer imaging agent conjugated to indocyanine green (ICG) and with an exquisitely pH-sensitive binary activation mechanism, may be used for tumor detection. ONM-100 micelles dissociate in acidic environments resulting in activation of the fluorescent ICG tag. As nearly all solid cancer types are acidotic, ONM-100 has the potential to act as a broadly indicated tumor agnostic imaging agent. This first-in-human study investigates the safety and feasibility of ONM-100 as a tumor agnostic imaging agent for intra-operative fluorescent imaging of various solid tumors. Methods: ONM-100 was IV administered 24±8h prior to surgery in a dose escalation scheme (0.1-1.2mg/kg). Patients with histopathologically confirmed breast cancer (BC), head and neck squamous cell carcinoma (HNSCC), colorectal cancer (CRC) and esophageal cancer (EC) were included. Blood was drawn to assess safety and pharmacokinetic data. Intra-operative fluorescence images were collected before and after tumor excision. Post-excision fluorescence images were obtained from serially sliced specimens and correlated with standard histopathological assessment. Results: 30 patients (11 BC, 13 HNSCC, 3 EC, 3 CRC) were enrolled. No ONM-100 related serious adverse events were observed and the agent was well-tolerated. A strong and sharply demarcated fluorescent signal was observed in all patients with vital tumor tissue (median CNR ranging 1.85-14.05) which correlated with tumor on final histopathology. HNSCC and superficially located BC as well as peritoneal metastasis could be clearly visualized in vivo during surgery. In four patients (BC and HNSCC), perioperatively, tumors otherwise unnoticed by the surgeons were detected on the margin or wound bed using fluorescence imaging. Additionally, two BC tumor lesions were detected that were missed by conventional pre-operative imaging and pathological assessment. Conclusions: ONM-100 appears to be safe and enables fluorescent visualization of tumors both in vivo and ex vivo. The first-in-human data demonstrate the feasibility for potential use of ONM-100 for image guided surgery, margin assessment and detection of occult disease. Clinical trial information: NTR 7085.
A functional measurement of MAPK pathway activation to predict response to MEK inhibitors in RAS-mutated patients.
Authors: Kato Shumei , Porter Robert , Okamura Ryosuke , Zelichov Ori , Tarcic Gabi , Vidne Michael , Kurzrock Razelle
Published: May 2019

3071

Background: MEK inhibitors can be used to treat patients with mutations that affect the MAPK pathway. Several MEK inhibitors are currently FDA-approved and effectively treat BRAF-mutated tumors, but RAS-mutated cancers are considered more resistant. However, it is unclear how the many distinct RAS variants impact the MAPK pathway and are affected by MEK inhibitors. We hypothesized that the level of MAPK pathway activation induced by different RAS mutations may predict response to MEK inhibition. Methods: Thirteen RAS mutations from 34 patients treated with MEK inhibitors at UCSD were synthesized, expressed in a HeLa-derived cell line and analyzed in vitro using a functional mutational analysis assay based on assessing downstream reporters in order to measure the activity of these mutations on the MAPK pathway. Each mutation received an activity score based on known oncogenic RAS mutation. Results: The most common type of cancer was colorectal cancer (N = 13). All patients received the MEK inhibitor, trametinib, based therapy. Patients were stratified into two groups: above an activity score of 1 (14 pts) or below it (20 pts). Median progression-free survival (PFS) after MEK inhibitor treatment correlated with higher MAPK activity score (9 vs 3 months; P = 0.041). Conclusions: Using a novel functional assay methodology for characterization of MAPK activation, we show that various RAS mutations activate the MAPK pathway to different levels. Higher activity is associated with longer PFS after MEK inhibitor treatment, suggesting that the relationship between signal transduction strength and clinical relevance merits additional exploration.
Observational, multicenter, prospective study to assess the impact on patients' outcome of a systematic screening of oncogenic drivers in advanced cancer: The GETHI XX-16 study.
Authors: Beato Carmen , Navarro Paloma , Rodriguez-Moreno JF , Navarro L Miguel , Jimenez Munarriz Beatriz , Bruixola Gema , Balana Carmen , Fenor MD , Fuster Jose , Zambrana Francisco , Sevillano Elena , Vila-Navarro Elena , NoguerÃ³n Esther , Mielgo Rubio Xabier , Viudez Antonio , Mediano Maria Dolores , Virizuela Juan Antonio , Ruiz Sergio , Mata Elena , Garcia-Donas Jesus ,   Spanish Groups for Orphan and Rare Cancer (GETHI)
Published: May 2019

3082

Background: Identification of “agnostic” genetic drivers in cancer is foreseen as a major step forward in precision medicine.Unfortunately, “off label” use of targeted therapies is not widely available and many oncogenic alteration do not present the same behaviour accross all tumor types.We aimed to analyze the real impact on patients management of the implementation of a systematic screening of genetic alterations in centers of the Spanish Group for Rare Cancer (GETHI). Methods: We designed an observational, prospective and multicenter study to molecularly characterize any adult patient with advanced cancer.Formalin fixed paraffin-embedded samples were studied by TrkA-C,ROS1 and ALK immunohistochemistry followed by RT-PCR when positive to confirm gene fusions. Additonally, the Next Generation Sequencing paltform ArcherFusion Plex (able to detect point mutations and rearrangements in 53 cancer related genes) was implemented.Clinical data regarding treatment administered and outcome, were collected from patients identified as harboring drugable alterations. Results: Up to 26 hospitals all over the country got involved in the study. 341 tumoral tissues, representing 41 different histologies were collected. Molecular studies could be performed in 292 samples that led to the identification of 33 patients as harboring somatic oncogenic mutations. 21 were considered druggable and 5 got targeted therapy directed against the alteration identified (three glioblastoma patients with EGFR mutations received erlotinib, one prostate cancer with a BRAF fusion received trametinib and one lung cancer with ALK translocation, previously deemed as negative by standard screening, received crizotinib). One of the glioblastoma patients achieved a long lasting stabilitation and both the prostate and lung tumors presented dramatic partial responses. Conclusions: Though only few cases harboring drugable alteratons got specif treatment, 50% achieved a meanignful benefit. A wide access to molecular screening and targeted drugs could improve the outcome of cancer patients.
Distinct radiological patterns of drug-induced pneumonitis (R-DIP) in early-phase clinical trials and predictive factors affecting outcome: A 10-year systematic review from the Royal Marsden Hospital Phase I Drug Development Unit experience.
Authors: Terbuch Angelika , Moreno Candilejo Irene , Scaranti Mariana , Bar Daniel , Estevez Timon Miriam , Ameratunga Malaka , Ang Joo Ern , Ratoff Jonathan , Minchom Anna , Banerji Udai , De Bono Johann S. , Tunariu Nina , Lopez Juanita Suzanne
Published: May 2019

3088

Background: We studied clinical and radiological parameters influencing DIP in patients (pts) participating in phase I clinical trials, aiming to investigate predictive factors affecting DIP, in particular those affecting outcome. Methods: 2439 consecutive stage IV cancer pts on phase I clinical trials from 2007 to 2017 were identified. Pts with respiratory symptoms or abnormal lung imaging were reviewed in detail, with longitudinal analysis of imaging by an experienced radiologist. R-DIP was categorized according to internationally recognized criteria. Results: 60 pts developed R-DIP (overall incidence 2.5%); most frequent in pts receiving drug conjugates (31.1%) followed by targeted therapies (8.3%). Hypersensitivity pneumonitis was most common (33.3%) followed by non-specific interstitial pneumonitis (30%) and cryptogenic organising pneumonitis (26.7%). 45% pts who developed R-DIP were clinically asymptomatic. The number of affected lobes (OR 1.47, 95% CI: 1.19-1.81, p < 0.001) and the pattern of R-DIP (OR 5.83 for ARDS, 95% CI: 0.38-90.26, p = 0.002) were significantly associated with a higher CTCAE pneumonitis grading. 23% pts (14/60) had investigational medicinal product (IMP) temporarily discontinued or had a dose reduction while 42% pts (25/60) had IMP permanently discontinued. 48% pts were treated with steroids. The number of affected lobes, pattern of R-DIP and steroid therapy did not influence an improvement in R-DIP (p = 0.65, 0.27 and 0.23 respectively). Continuation of treatment resulted in worsening of DIP in 42.9% of cases. The only predictive factor for an improvement in DIP was an interruption of treatment (OR 0.05, 95% CI: 0.01-0.35, p = 0.01). 14 pts were retreated with a reoccurrence of R-DIP in 4 pts (28.6%). Conclusions: R-DIP from novel agents in early phase clinical trials presents in varied radiological patterns, with findings often preceding clinical symptoms. Treatment interruption leads to improvement of DIP and should be considered early. Close clinical and radiological surveillance is recommended should IMP be restarted.
Phase 1 of ABTL0812, a proautophagic drug, in combination with paclitaxel and carboplatin at first-line in advanced endometrial cancer and squamous cell lung carcinoma.
Authors: Farinas-Madrid Lorena , Estévez-García Purificación , Perez-Fidalgo Jose Alejandro , Bosch-Barrera Joaquim , Moran Teresa , Nadal Ernest , Rodriguez Freixinos Victor , Calvo Elisa , Falcon Alejandro , Martín-Martorell Paloma , Huerta Alvaro Marisol , Barretina-Ginesta Maria Pilar , Romeo Margarita , Gil-Martin Marta , Garralda Elena , Rodon Jordi , Lizcano Jose M. , Domenech Carles , Alfon Jose Alberto , Oaknin Ana
Published: May 2019

3089

Background: ABTL0812 is a novel anti-cancer agent that induces a strong autophagy-mediated cell death by a dual mechanism. It inhibits the Akt/mTOR axis by upregulating TRIB3, an endogenous Akt inhibitor, and induces reticular (ER)-stress. Preclinical data in squamous non-small cell lung carcinoma (Sq-NSCLC) and endometrial cancer (EC) has indicated drug efficacy as a single agent and potentiation of chemotherapy. Methods: A phase 1 clinical study was designed where ABTL0812 was administered orally in combination with 175 mg/m2 paclitaxel/carboplatin AUC5 D1 every 3 weeks (P/C), and posterior ABTL0812 as a maintenance therapy until disease progression or unacceptable toxicity. The study included first-line patients (pts) with advanced Sq-NSCLC or advanced/recurrent EC. The design included a 3+3 de-escalation trial followed by an expansion cohort, where the starting dose of ABTL0812 was 1300 mg tid and if at least 2 pts experienced a DLT, the dose level would be de-escalated to 1000 mg tid. Safety and tolerability were the primary endpoints and preliminary efficacy according to RECIST v1.1 criteria and pharmacodynamic biomarkers (TRIB3 and CHOP an ER-stress biomarker, by qPCR in whole blood) were the secondary endpoints. Results: 16 EC and 5 Sq-NSCLC pts were enrolled. One DLT, a grade 4 neutropenia, appeared in the first cohort of 6 pts and no de-escalation was applied. Fourteen pts were included in an expansion cohort with the same dose level (1300 mg tid), and 1 DLT, a grade 3 febrile neutropenia, was observed. Therefore, the dose of 1300 mg tid was selected as RP2D in combination with P/C. Most frequent grades 2-4 AEs were neutrophil count decreased (n = 9, 43%), nausea (n = 5, 24%), fatigue (n = 4, 19%), followed by anemia, vomiting, dyspepsia, platelet count decreased, arthralgia and neurotoxicity (n = 2, 10% each). Seventeen pts (13 EC and 4 Sq-NSCLC) who completed at least two treatment cycles were evaluable for efficacy; 1 CR (EC), 8 PR (7 EC and 1 Sq-NSCLC), 7 SD (5 EC and 2 Sq-NSCLC) and 1 PD (Sq-NSCLC) were observed. Pharmacodynamic biomarkers showed increased TRIB3 and CHOP levels. Conclusions: The combination of ABTL0812+P/C was safe and tolerated, efficacy signals were observed, and biomarker modulation confirmed drug activity. The triple combination is currently being evaluated in both indications in a Phase 2 study. Clinical trial information: NCT03366480.
A phase Ib study of prexasertib, a checkpoint kinase (CHK1) inhibitor, and LY3023414, a dual inhibitor of class I phosphatidylinositol 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) in patients with advanced solid tumors.
Authors: Hong David S. , Moore Kathleen N. , Bendell Johanna C. , Karp Daniel D. , Wang Judy Sing-Zan , Ulahannan Susanna Varkey , Johnson Melissa Lynne , Aljumaily Raid , Hynes Scott , Callies Sophie , Decker Rodney , LaBell Elizabeth , Niland Michele , Wang Xuejing Aimee , Bence Lin Aimee , Patel Manish R.
Published: May 2019

3091

Background: Prexasertib inhibits CHK1, a kinase involved in DNA repair and replication. LY3023414 inhibits PI3K/mTOR signaling, implicated in the development of malignant disease. Prexasertib + LY3023414 has resulted in enhanced antitumor activity in triple negative breast cancer (TNBC) in vitro models. Methods: This Phase 1b study in patients (pts) with solid tumors assessed escalating doses of prexasertib (60-105 mg/m2 IV every 14 days [q14d]) and LY3023414 (100-200 mg orally twice daily [BID]). Dose escalation ceased once the maximum tolerated dose of each monotherapy was reached. An initial expansion cohort (Arm E) explored prexasertib 105 mg/m2 q14d + LY3023414 200 mg BID. Subsequent expansion cohorts evaluated prexasertib 105 mg/m2 q14d + LY3023414 150 mg BID in pts with solid tumors with PIK3CA mutations (Arm E2) or TNBC (Arm E3). Results: Fifty pts were enrolled (escalation: n = 13; Arm E: n = 9; Arm E2: n = 15; Arm E3: n = 13). No dose-limiting toxicities (DLTs) were observed during escalation however DLT-equivalent toxicities were observed in 2 pts in Arm E (anemia, neutropenia, thrombocytopenia, oral mucositis, abdominal pain, fatigue). Due to toxicity, a reduced dose of LY3023414 (150 mg BID) was assessed in Arm E2/E3. In the 28 patients treated in Arms E2/E3, common treatment-related adverse events (any grade; grade ≥3) were: leukopenia/neutropenia (82%; 79%), thrombocytopenia (46%; 36%), nausea (46%; 0%), stomatitis (39%, 4%), vomiting (36%; 0%), and anemia (29%; 18%). Febrile neutropenia was reported in 25% of pts. Dose reductions in Arm E2/E3 were common. In escalation, 2 pts achieved a partial response (PR) and 3 pts achieved stable disease (SD). In Arm E, 78% of pts achieved SD. Of the pts evaluable at the time of data transfer, PRs were achieved in 1 pt with an unknown primary (Arm E2) and 2 pts with TNBC (Arm E3). Each agent’s pharmacokinetic profile was consistent with prior monotherapy data. Conclusions: Prexasertib + LY3023414 showed preliminary efficacy in heavily pretreated pts with solid tumors but was associated with toxicity, suggesting supportive care may be required. Clinical trial information: NCT02124148.
A phase I study of the APE1 protein inhibitor APX3330 in patients with advanced solid tumors.
Authors: Shahda Safi , Lakhani Nehal J. , O'Neil Bert , Rasco Drew W. , Wan Jun , Mosley Amber L , Liu Hao , Kelley Mark R. , Messmann Richard Adam
Published: May 2019

3097

Background: APX3330 is an orally administered anti-cancer, anti-CIPN agent targeting the APE1 protein. APE1 maintains NFkB, STAT3, AP-1 and HIF-1a in a reduced form, acting as a regulator of transcription factors. A dual function protein, APE1 also plays a role in protecting against oxidative DNA damage in neurons. APX3330 is a highly selective inhibitor of APE1 redox function in tumors that enhances the neuronal protection function of APE1. Methods: We report on study NCT03375086 evaluating APX3330 in patients with incurable malignancies. Eligibility required adequate organ function, PS 0-2 and tumors not amenable to curative therapy. 1° and 2° objectives included determining the recommended phase 2 dose (RP2D), the safety and PK/PD profiles of APX3330 and reporting any RECIST anti-tumor activity. Patients received APX3330 b.i.d, in 21-day cycles. AE evaluation included 1 pt/cohort until the occurrence of ≥ G2 toxicity at which time the study proceeded in a 3+3 design. Additional patient were also recruited in cohorts in order to attain PK/PD and biopsy samples. Results: Between 2/18 and 8/18, 19 subjects (13M, 6F) with median age of 69 y started therapy. Dose (mg/d) escalation and number of patients treated (n) per each cohort proceeded as follows: 240 mg (1), 360 (4), 480 (2), 600 (6) and 720 (6). APX3330 was well tolerated at dose levels from 240-600 mg/d. The most frequent treatment-related adverse event (all grades) was G1 fatigue. A G3 rash occurred in two subjects at the 720 mg level defining 600 mg/d as the RP2D for further development. Six subjects had disease stabilization for ≥ 4 cycles, and of these, four subjects with the following diagnosis, RECIST response and days on study included: (CRC, PR, 356), (Endometrial, SD, 316), (Melanoma, SD, 245), (Prostate, SD, 246). Final PK and PD data, including proteomic, transcriptome, APE1 serum levels and CTC analyses are pending and will be reported at the conference. Conclusions: APX3330 is an orally administered inhibitor of APE1. This phase I study identified 600 mg PO daily as the RP2D for further development. RECIST evaluation identified signs of clinical activity in this un-selected population of patients with advanced cancer. PD analyses indicate APX3330 mediated targeting of the APE1 protein. Clinical trial information: NCT03375086.
First-in-human phase I trial of anti-hepatocyte growth factor (HGF) antibody (YYB101) in refractory solid tumor patients: Integrative pathologic-genomic analysis and the final results.
Authors: Lee Jeeyun , Kim Seung , Nam Do-Hyun , Lee Su Jin , Park Se Hoon , Park Joon Oh , Lee Jeong-Won , Kim Kyoung-Mee , Lee Hukeun , Park Neunggyu , Kim Hoon-Kyo , Lee Song-Jae , Song Seong-Won , Kim Jung Ju , Park Young Suk , Lim Ho Yeong , Kang Won Ki
Published: May 2019

3104

Background: It has been demonstrated in vivo that HGF-MET signaling axis is a key molecular determinant in tumor invasion and there is a significant association in HGF expression and mesenchymal phenotype in addition to immune cell recruitment. We have developed a HGF neutralizing humanized monoclonal antibody antibody, YYB-101. The aim of this study was to determine the maximum tolerate dose (MTD), safety, pharmacokinetics (PK), and pharmacodynamics (PD) of YYB101, in patients with refractory solid tumors. Methods: YYB101 was administered intravenously at once every 2 weeks doses of 0.3, 1, 3, 5, 10, 20, 30 mg/kg, according to a 3+3 dose escalation design. Enrolled patients were planned to receive YYB101 until disease progression or intolerable toxicity. The escalation and expansion cohorts (20mg/kg) were completed. Pre-planned biomarker analysis was performed in parallel. Results: 39 heavily pre-treated refractory cancer patients were enrolled and received YYB101. No DLT was observed. YYB101 demonstrated dose proportional PK up to the dose of 30 mg/kg. No patients discontinued treatment because of adverse events. Based on PK analysis and toxicity data, the recommended dose was determined as 20 mg/kg. Of 39 evaluation patients, there was 1 confirmed partial response for > +14months (2.5%, N = 1; 1 (of 2) sebaceous carcinoma) and 17 stable disease as best response (43.5%, N = 17; 7 (of 13) CRC, 3 (of 4) melanoma, 1 (of 2) sebaceous carcinoma, 1 (of 3) gastric, 1 (of 1) basal cell carcinoma, 2 (of 10) ovarian cancer, 1 (of 1) HCC, 1 (of 1) lung cancer). Of note, 1 sebaceous carcinoma patient who have failed to ≥2+ lines of chemotherapy, have been responding to YYB for 14 months. The MET and HGF expressions by immunohistochemistry (IHC) were evaluated in 19 and 17 tumor specimens, respectively. Neither protein expressions were significant predictors for treatment response to anti-HGF antibody. However, we have observed significant reduction in HGF in responders to YYB. Two long-term responders had mesenchymal signature in RNA sequencing. Conclusions: YYB101 has a favorable safety profile in patients with refractory solid tumors and a dose-proportional PK. Efficacy data are encouraging and phase II combination therapy with YYB101 is planned to be open in metastatic CRC patients as salvage treatment. The predictive power of mesenchymal signature in YYB responders will be defined prospectively. Clinical trial information: 02499224.
Clinical, pathological and genetic predictors of patient-derived xenograft (PDX) engraftment in EGFR-mutated lung adenocarcinoma (LUAD).
Authors: Martins-Filho Sebastiao N. , Weiss Jessica , Pham Nhu-An , Cabanero Michael , Fares Aline Fusco , Stewart Erin L. , Patel Devalben , McConnell Judy , Bradbury Penelope Ann , Sacher Adrian G. , Leighl Natasha B. , Grindlay Alexandria , Allison Frances , LI Ming , Yasufuku Kazuhiro , Shepherd Frances A. , Moghal Nadeem , Tsao Ming Sound , Liu Geoffrey
Published: May 2019

3110

Background: PDX are useful preclinical models to study drug response and resistance. Different specimen types have been used to generate PDX models including histological (surgery and CT-guided biopsy) and cytological preparations (EBUS and pleural effusions). We hypothesize that engraftment is not stochastic and is affected by many factors including sample type and tumor pathological and molecular properties. To improve sample selection and cost-effectiveness of PDX experiments, we investigated clinical, histological and genetic correlates of engraftment in EGFR-mutated LUAD. Methods: We assessed PDX engraftment from 96 surgical resections, 13 CT-guided biopsies, 21 EBUS and 14 pleural effusions of EGFR-mutated LUAD. Sixty-five samples, including 6 engrafted (XG) and 54 non-engrafted (noXG) were evaluated by exome sequencing. Results: Engraftment was successful in 9/96 (9%) surgical resections, 6/13 (46%) CT-guided biopsies, and 0/35 cytological samples. Biopsies taken at time of treatment failure (compared to treatment naive biopsies) correlated with greater engraftment (p=0.007, AUC = 0.68). Multivariable regression analysis of clinical variables at the time of sampling identified advanced (vs early) stage (p = 0.003) and histological (vs cytological) preparations (p < 0.001) as the strongest predictors of engraftment (AUC = 0.79). Among tumor histologic features, solid (vs lepidic, acinar and papillary) pattern was associated with greater engraftment (p < 0.001). Presence of EGFR-T790M (p = 0.004) and TP53 (p = 0.009) mutations were associated with greater engraftment; all XG samples carried TP53 mutations. EGFR-Ex19del (p = 0.076) showed a trend towards engraftment whereas EGFR-L858R (p = 0.086) trended towards non-engraftment. Conclusions: Advanced stage, post-therapy tumors, T790M+ and TP53+ EGFR-mutated LUAD samples obtained for histological processing are more likely to engraft as PDXs. Despite low engraftment rates, these models are useful to study novel therapeutic strategy and elucidation of resistance mechanisms.
Genomic somatic alterations of human epidermal growth factor-2 (HER2) gene: A pan-cancer analysis.
Authors: Zhu Xinhua , Zhou Yong , Zhang Yuzi , Cai Shangli
Published: May 2019

3112

Background: Human epidermal growth receptor 2 (HER2) is a well-known oncogenic drive gene with multiple targeted therapeutic options. In this study, we aim to assess the landscape of HER2 alterations in solid tumors and evaluate the feasibility of circulating tumor DNA (ctDNA) tested by next-generation sequence (NGS) as a tool to detect HER2 alterations. Methods: Alterations of HER2 by NGS (Illumina NextSeq 500) were queried in 3D Medicines database. The mean depth of tissue and circulating tumor DNA (ctDNA) test was 500X and 5000X, respectively. 11,013 patients tested using tumor tissue and 6,970 patients tested using ctDNA were included in this analysis. Results: Of 11,013 patients tested using tumor tissue, any HER2 and known or likely deleterious HER2 mutations were identified in 739 (6.7%) and 531 (4.8%) patients, respectively. Of 531 patients who carried known or likely deleterious HER2 mutations, 263 (49.5%) had HER2 amplification and 259 (48.8%) had single nucleotide variations (SNVs). Across all tumor types, breast cancer was found to have the highest frequency of HER2 amplification (14.9%, 48/323), followed by gastric cancer (6.6%, 31/470) and biliary tract cancer (5.8%, 33/571). Moreover, 11% (8/73) of duodenal cancer, 4.5% (7/154) of urothelial cancer, 3.8% (18/470) of gastric cancer, 3.1% (142/4555) of lung cancer, 2.9% (17/571) of biliary tract cancer, 2.8% (44/1562) of colorectal cancer and 2.7% (9/323) of breast cancer carried known or likely deleterious HER2 SNVs. Of 6970 patients tested using ctDNA, any HER2 and known or likely deleterious HER2 mutations were identified in 592 (8.5%) and 277 (4.0%) patients, respectively. In the ctDNA cohort, 15.7% (36/230) of breast cancer and 3.1% (5/161) of biliary tract cancer carried HER2 amplification. However, 11.6% (20/173) of gastric cancer had HER2 amplification tested by ctDNA which was higher than that tested using tissue. Furthermore, 5.6% (13/230) of breast cancer, 4.5% (2/44) of urothelial cancer, 3.4% (6/173), 2.5% of biliary tract cancer and 2.0% (94/4586) lung cancer harbored known or likely deleterious HER2 SNVs in ctDNA cohort. Conclusions: HER2 alterations existed across tumor types and the landscape of genomic alterations in HER2 gene varied according to different type of tumor. In addition, ctDNA can be used as a potential tool to detect HER2 alterations.
Development and clinical validation of Lantern Pharma’s AI engine: Response algorithm for drug positioning and rescue (RADR).
Authors: Kathad Umesh , Vedaraju Yuvanesh , Kulkarni Aditya , Tobin Gregory , Sharma Panna
Published: May 2019

3114

Background: The Response Algorithm for Drug positioning and Rescue (RADR) technology is Lantern Pharma's proprietary Artificial Intelligence (Al)-based machine learning approach for biomarker identification and patient stratification. RADR is a combination of three automated modules working sequentially to generate drug- and tumor type-specific gene signatures predictive of response. Methods: RADR integrates genomics, drug sensitivity and systems biology inputs with supervised machine learning strategies and generates gene expression-based responder/ non-responder profiles for specific tumor indications with high accuracy, in addition to identification of new correlations of genetic biomarkers with drug activity. Pre-treatment patient gene expression profiles along with corresponding treatment outcomes were used as algorithm inputs. Model training was typically performed using an initial set of genes derived from cancer cell line data when available, and further applied to patient data for model tuning, cross-validation and final gene signature development. Model testing and performance computation were carried out on patient records held out as blinded datasets. Response prediction accuracy and sensitivity were among the model performance metrics calculated. Results: On average, RADR achieved a response prediction accuracy of 80% during clinical validation. We present retrospective analyses performed as part of RADR validation using more than 10 independent datasets of patients from selected cancer types treated with approved drugs including chemotherapy, targeted therapy and immunotherapy agents. For an instance, the application of the RADR program to a Paclitaxel trial in breast cancer patients could have potentially reduced the number of patients in the treatment arm from 92 unselected patients to 24 biomarker-selected patients to produce the same number of responders. Also, we cite published evidence correlating genes from RADR derived biomarkers with increased Paclitaxel sensitivity in breast cancer. Conclusions: The value of RADR platform architecture is derived from its validation through the analysis of about ~17 million oncology-specific clinical data points, and ~1000 patient records. By implementing unique biological, statistical and machine learning workflows, Lantern Pharma's RADR technology is capable of deriving robust biomarker panels for pre-selecting true responders for recruitment into clinical trials which may improve the success rate of oncology drug approvals.
Accumulation of active metabolite M-2 predicts overall survival (OS) of chemorefractory metastatic colorectal cancer patients treated with regorafenib (REGO).
Authors: Rousseau Benoit , Boukerma Arezki Khaled , Henriques Julie , Cohen Romain , Lucidarme Olivier , Borg Christophe , Tournigand Christophe , Kim Stefano Chong Hun , Bachet Jean-Baptiste , Mazard Thibault , Louvet Christophe , Chibaudel Benoist , Diaz Luis A. , Vernerey Dewi , Andre Thierry , Hulin Anne
Published: May 2019

3121

Background: TEXCAN, a prospective phase II GERCOR study of treatment with REGO in chemorefractory metastatic colorectal cancer (mCRC) patients (NCT02699073) included a prospective pharmacokinetic (PK) ancillary study aiming to investigate correlations between OS and concentrations (C) of REGO and its active metabolites M-2 and M-5. Methods: 55 patients were included, with the same inclusion/exclusion criteria as CORRECT (NCT01103323), and treated orally with 160 mg REGO daily for 3 weeks on and 1 week off. 34 patients had PK samples at C1D15 and 26 at C2D15 for Cmin. REGO, M-2 and M-5 Cmin were measured by LC-MS/MS. PK analyses studied the link between OS and PK parameters: Cmin of REGO, M-2 and M-5 at C1 and accumulation of pharmacological active metabolites between C1 and C2, assessed by the C2/C1 ratio of M-2 or M-5 Cmin concentrations. Results: REGO, M-2 and M-5 Cmin [median (Q1-Q3)] were respectively 1.99 (1.03-2.73), 1.44 (0.89-2.49) and 1.61 (0.79-2.37) mg/L at C1D15 and 1.90 (1.10-2.76), 1.29 (0.77-2.24) and 1.17 (0.45-2.42) mg/L at C2D15. C2/C1 M-2 ratio and M-5 ratio medians were 0.82 (0.50-1.78) and 0.75 (0.41-1.93), respectively. Univariate analyses showed a major OS benefit in patients with C2/C1 M-2 ratio ≥median vs < median (12.6 vs 4.0 months respectively, hazard ratio = 0.35, 95% confidence interval 0.14-0.86, p-value = 0.023) but not for C2/C1 M-5 ratio ≥median. Multivariate analyses, including the CORRECT REGOSCORE groups, showedan independent 66% reduction in death risk in the group of patients with C2/C1 M-2 ratio ≥median. The C2/C1 M-2 ratio correlated with C1 REGO+M-2+M-5 (Csum) (0.53, p-value = 0.006). Restricted Cubic spline analysis showed an increased OS benefit as the C2/C1 M-2 ratio rises and when C1 Csum ranged between 2.5 and 5.5 mg/L. PK parameters were not associated with toxicities. Conclusions: M-2 accumulation between C1 and C2 is independently associated with improved OS in mCRC patients treated by REGO. M-2 accumulates and OS is favorable when C1 REGO+M-2+M-5 sum ranged between 2.5 and 5.5 mg/L. These results may lead to develop individual REGO dosage modification strategies based on PK monitoring. Clinical trial information: NCT02699073.
Larotrectinib efficacy and safety in adult TRK fusion cancer patients.
Authors: Hong David S. , Kummar Shivaani , Farago Anna F. , Lassen Ulrik Niels , Berlin Jordan , Schilder Russell J. , McDermott Raymond S. , Patel Jyoti D. , Dowlati Afshin , Doebele Robert Charles , Tan Daniel Shao-Weng , Lee James J. , Nanda Shivani , Childs Barrett H. , Ku Nora , Drilon Alexander E. , Hyman David Michael
Published: May 2019

3122

Background: A broad range of pediatric and adult malignancies harbor TRK fusions involving the NTRK1, NTRK2, and NTRK3 genes. The highly-selective TRK inhibitor, larotrectinib, has previously shown a high overall response rate (ORR) and a favorable safety profile in patients (pts) with TRK fusion cancer. To better delineate efficacy in adults, as pediatric pts have a particularly high ORR, here we report updated efficacy and safety data from the adult subset of pts with TRK fusion cancer treated with larotrectinib. Methods: Adult pts (aged 18 or older) with TRK fusion cancer detected by local testing in 2 larotrectinib clinical trials (NCT02122913 and NCT02576431) were analyzed. Larotrectinib was administered 100 mg PO BID until disease progression, withdrawal, or unacceptable toxicity. Disease status was assessed by both investigator (INV) and independent assessment (IRC) using RECIST v1.1. Results: As of July 30, 2018, 83 adults (median age: 57 y, range 20–80 y) with TRK fusion cancer had been treated. Cancer types included salivary gland (23%) and thyroid cancer (19%), soft tissue sarcoma (14%), lung cancer (13%), colon cancer and melanoma (7% each), GIST (5%), and bone sarcoma, cholangiocarcinoma, and appendiceal, breast, and pancreas cancer (≤2% each). TRK fusions involved NTRK1 (40%), NTRK2 (2%), and NTRK3 (57%). 77% of pts had received prior systemic therapy (median lines: 2, range 0–10). In 74 pts evaluable per INV, the ORR was 76% with 9% CR, 57% confirmed PR, 9% PR pending confirmation, 12% SD, 11% PD, and 1% not determined; 9 pts were non-evaluable (NE) due to lack of post-baseline assessment. In 65 pts evaluable per IRC, the ORR was 68% with 17% CR, 51% PR, 15% SD, 12% PD, and 5% NE. With a median follow up of 17.2 and 17.5 mo per INV and IRC, respectively, the median duration of response had not been reached (ranges identical: 1.9+ to 38.7+ months). At data cutoff, 63% remained on treatment; 30% had discontinued due to disease progression. Adverse events were mostly grade 1–2. Conclusions: Larotrectinib demonstrated robust tumor-agnostic efficacy and a favorable safety profile in adult pts with TRK fusion cancer. These results support testing for TRK fusion cancer in pts with advanced solid tumors, regardless of site of primary diagnosis. Clinical trial information: NCT02122913 and NCT02576431.
Clinicopathologic characteristics of NRG1 fusion-positive cancers: A single-institution study.
Authors: Schram Alison M. , Benayed Ryma , Somwar Romel , Rekhtman Natasha , Arcila Maria E. , Ladanyi Marc , Hyman David Michael , Drilon Alexander E.
Published: May 2019

3129

Background: NRG1 rearrangements are oncogenic drivers across several tumor types. Chimeric proteins encoded by NRG1 fusions activate HER3, resulting in heterodimerization with HER2 and activation of downstream signaling. Preclinical and preliminary clinical data suggest that targeting HER3 may be an effective treatment strategy for patients with NRG1 fusion-positive tumors. We aimed to describe the clinical and genomic characteristics of patients identified at our institution with NRG1 fusions. Methods: We analyzed results from prospective targeted exome and/or RNA sequencing performed at Memorial Sloan Kettering between 2014-2018 involving > 30,000 samples. NRG1 fusion-positive tumors were identified and these cases were manually reviewed. Results: NRG1 fusions were detected in 24 patients. Cancer types included lung (N = 9), pancreas (N = 7), breast (N = 5), prostate (N = 1), gallbladder (N = 1), diffuse large B-cell lymphoma (N = 1), and cancer of unknown primary (N = 1). 6/9 lung cancers had mucinous differentiation. The majority of patients were Caucasian (N = 17), half were female (N = 12) and ages ranged from 24-82 years-old. Targeted exome sequencing identified the fusion in 10/23 cases tested, including 2 not confirmed by RNA. The remaining 14 were detected using RNA. Fusion partners included CD74 (N = 6), SLC3A2 (N = 2), SDC4 (N = 2), ATP1B1 (N = 2), FOXA1 (N = 1), SLCA4 (N = 1), ROCK1 (N = 1), TNKS (N = 1), CCND1 (N = 1), PAK1 (N = 1), STAU3 (N = 1), RAD51 (N = 1), CD44 (N = 1), NCOR1 (N = 1), RBPMS (N = 1), and WHSC1L1 (N = 1). Pancreas cancers were KRAS wild-type and lung cancers had no co-occurring alterations in ALK, ROS1, EGFR, RET, MET, RAS, or RAF. All tumors were microsatellite stable. A durable response was achieved with anti-HER3 antibody therapy (GSK2849330) in a patient with a CD74- NRG1-rearranged invasive mucinous adenocarcinoma (previously reported). Four patients treated with an irreversible small molecule HER2 inhibitor (afatinib) did not respond to treatment, suggesting direct targeting of HER3 may be superior to HER2 inhibition in patients with NRG1 fusion-positive tumors. Conclusions: NRG1 fusions occur in several tumor types and may be amenable to targeting with HER3-directed therapy.
Actionable coalterations in breast tumors with pathogenic mutations in the homologous recombination DNA damage repair pathway.
Authors: Heeke Arielle Lutterman , Xiu Joanne , Lynce Filipa , Pohlmann Paula Raffin , Vidal Gregory A. , Isaacs Claudine , Swain Sandra M. , Schwartzberg Lee S. , Tan Antoinette R.
Published: May 2019

3132

Background: Homologous recombination (HR) deficient breast tumors may have genomic alterations that suggest responsiveness to targeted therapies other than PARP inhibitors. Methods: Comprehensive molecular profiles of 4,647 breast tumors performed at Caris Life Sciences using 592-gene NGS (average read depth 500X) were reviewed to identify somatic pathogenic mutations in HR genes ARID1A, ATM, ATRX, BAP1, BLM, BRCA1/2, BRIP1, CHEK1/2, FANCA/C/D2/E/F/G/L, KMT2D, MRE11, NBN, RAD50/51/51B & PALB2, as well 41 markers associated with treatment response. Results: Overall, 17.9% of breast tumors have HR mutations (HR-MT, 831/4647). HR-MT is seen most in HER2– disease [hormone receptor (hr)+/HER2– (18.3%, n=2183), TNBC (18.2%, n=1568), hr–/HER2+ (12.9%, n=217)]. Mean TMB is higher for HR-MT tumors across subtypes (9.2 mut/Mb vs 7.6 WT, p=<0.0001) & independent of MS status. HR-MT hr–/HER2+ tumors are more likely to have PD-L1 overexpression (25% vs 13.1% hr–/HER2+ WT, p=0.10), whereas MSI is more prevalent in HR-MT HER2– (hr+/HER2– 2.3%, TNBC 1.4%, HER2+ 0%). Mutations in chromatin remodeling genes (*) are more common in HR-MT. Additional co-alterations are outlined in the Table. Conclusions: In breast cancer, HR-MT is associated with HER2– disease & markers of response to immunotherapy. Clinical trials combining HRD targeted agents & immunotherapy are underway & could be enriched through comprehensive molecular profiling. Mutations were identified in both HR-MT & HR WT tumors that suggest other targets for treatment. [Table: see text]
MET exon 14 skipping analogs: Rare but potentially clinically actionable.
Authors: Feldman Rebecca , Ellis Michelle , Swensen Jeffrey , Korn Wolfgang Michael , Gatalica Zoran
Published: May 2019

3141

Background: The DpY motif within the exon 14 juxtamembrane domain of the MET receptor gene is critical for Cbl-mediated negative regulation. Splicing alterations that delete this residue, known as exon 14 skipping mutations (ex14sk mt), lead to prolonged MET protein stability and oncogenic signaling. Specific mt at the Y1021 (aka 1003) residue are thought to lead to similar effects as ex14sk, but due to their rarity, their role in NSCLC is unknown. We sought to identify and characterize non-ex14sk mt that include/surround Y1021. Methods: Retrospective review of molecular profiles for non-ex14sk mt that include/surround the DpY motif (Y1021) in MET. Two NGS platforms were included: MiSeq (2014-2017; n=2865) and NextSeq (2017-2019; n=6084). Immunohistochemistry (IHC) of cMET (SP44) and co-occurring alterations (EGFR, KRAS, ALK, ROS) were also reviewed. Results: Of 8,949 NSCLC patients with successful NGS of MET gene by either platform, 13 cases or 0.2% were identified to have an alteration within the amino acids of interest. Eleven cases included substitutions at Y1021 (5 phenylalanine, 4 histidine and 3 arginine) and the remaining two cases included small insertion-deletions p.E1017_Y1021delinsH and p.D1020_Y1021delinsV, the latter was later excluded as it co-harbored an ex14sk mt. Conclusions: Similar to patients with ex14sk mt, substitutions and small indels at Y1021 exhibit Clinicopathological features such as previous smoking history and older age, mutual exclusivity with oncogene drivers and MET protein overexpression. The rarity of these analogous ex14sk mt suggests deletions of exon 14 provide cellular advantages beyond Cbl-mediated ubiquitinylation of MET. Although rare, the impact of these mt on efficacy of Met-directed therapy deserves further exploration.[Table: see text]
Association of colon cancer (CC) molecular signatures with prognosis and oxaliplatin prediction-benefit in the MOSAIC Trial (Multicenter International Study of Oxaliplatin/5FU-LV in the Adjuvant Treatment of Colon Cancer).
Authors: Pogue-Geile Katherine L. , Andre Thierry , Song Nan , Lipchik Corey , Wang Ying , Kim Rim S. , Feng Huichen , Gavin Patrick , Van Laethem Jean-Luc , Srinivasan Ashok , Hickish Tamas , Jacobs Samuel A. , Tabernero Josep , Lucas Peter C. , De Gramont Aimery , Wolmark Norman , Flejou Jean-François , Paik Soonmyung
Published: May 2019

3503

Background: MOSAIC and C-07 showed that oxaliplatin (OX) added to 5-fluorouracil plus leucovorin significantly improved disease free survival (DFS). However, OX is associated with neurotoxicity and the vast majority of patients do not receive OX-benefit; highlighting the importance of an OX-benefit predictor. In C-07, colon tumors with a CRCA (Colorectal Cancer Assigner) stem-like subtype were associated with a poor prognosis and no OX-benefit, but stage III patients with an enterocyte subtype did. We tested the association of CRCA and CMS molecular subtypes with prognosis and OX-benefit in stage III MOSAIC patients. Also, recombination proficiency scores (RPS) were tested for the same associations. RPS scores quantify the efficiency of DNA-damage repair. Low RPS have been associated with inferior overall survival (OS) in non-small cell lung carcinoma patients treated with surgery alone but better OS for patients who received surgery plus chemotherapy. Methods: Gene expression profiles from 590 stage III pts with follow up were successfully profiled by a custom designed nCounter code set. CRCA subtypes were determined by a locked down algorithm based on a re-estimated centroid using 72 genes (Song et al 2016). CMS subtypes were determined by modified single sample predictor (SSP) using 84 genes. RPS scores were determined as previously described by Pitroda et al (2014). Signature predictions were made while blinded to clinical outcome and signature performance was evaluated while blinded to gene expression. Results: The stem-like subtype was associated with a very poor prognosis (Stem-like vs others HR=1.56, p<0.01) and no OX-benefit. CRCA and CMS subtypes did not associate with OX-benefit. Using a median cut point, stage III patients with low RPS scores received significant OX-benefit (HR=0.67, p=0.033, N=290) and patients with high RPS scores did not (HR=1.2, p=0.32, N=300) with significant interaction p=0.025. Conclusions: The observation in C-07, that the stem-like subtype has the poorest prognosis and did not receive OX-benefit, was validated in MOSAIC, identifying patients who need new therapies. RPS scores may help to identify the subset of patients with OX-benefit in stage III CC, confirmation of this observation is currently being investigated in C-07. Support: PA DoH; NSABP; Sanofi.
A multicenter randomized phase III trial of capecitabine with or without irinotecan driven by UGT1A1 in neoadjuvant chemoradiation of locally advanced rectal cancer (CinClare).
Authors: Zhang Zhen , Sun Xinchen , Liu Anwen , Zhu Yuan , Zhu Yaqun , Zhang Tao , Jia Jianhui , Tan Shisheng , Wu Junxin , Zhou Juying , Wang Xin , Yang Jialin , Zhao Yuanyuan , Zhang Hongyan , Zhang Chen , Cai Gang , Zhu Ji
Published: May 2019

3510

Background: Our phase I/II study identified irinotecan dose differentiated by UGT1A1 genotype in the neoadjuvant CRT and showed improved pCR. The objective of this phase III study was to further investigate irinotecan combined with capecitabine-based chemoradiotherapy as preoperative treatment for locally advanced rectal cancer. Methods: We underwent a prospective, randomized, open-label, multicenter, phase 3 trial in China from Nov.2015 to Dec.2017. Eligible patients with clinical stage T3-4 and/or N+ rectal adenocarcinoma were randomly allocated to two arms. The approach in control arm (Arm A, n = 180) was pelvic radiation of 50 Gy/25 fractions with concurrent capecitabine 825 mg/m2 twice daily 5 days per week, followed by a cycle of XELOX two weeks after the end of CRT. The experimental arm (Arm B, n = 180) was pelvic radiation with capecitabine 625 mg/m2 twice daily 5 days per week and combined with weekly irinotecan. The irinotecan dose was used based on UGT1A1 genotype of 80mg/m2 for UGT1A1*1*1 or 65mg/m2 for UGT1A1*1*28 weekly, followed by a cycle of XELIRI. The primary endpoint is pathological complete response (pCR). This trial was registered with ClinicalTrials.gov, number NCT02605265. Results: Surgery was performed in 86.5% and 88.2% of patients in two groups, with 38.9% and 30.5% of patients got abdominoperineal resection respectively. The pCR rate was 17.5% in Arm A and 33.8% in Arm B (P = 0.001). Four and 6 patients maintained a complete clinical response status at least 12 months and were marked as cCR. The CR rate, including pCR and cCR, was 17.4% in Arm A and 33.1% in Arm B (P = 0.001). The most common grade 3-4 adverse events during preoperative treatment were leucopenia (3.4% vs. 25.3%), neutropenia (1.7% vs. 19.7%) and diarrhea (1.7% vs. 13.5%) in two arms. The overall rate of surgical complications were not significantly different between arms (11.0% vs. 14.6%). Conclusions: Adding irinotecan guided by UGT1A1 to capecitabine-based neoadjuvant chemoradiotherapy significantly increases complete tumor response. The treatment toxicities were increased but tolerable. This treatment can be as an option for ‘watch and wait’ approach. Clinical trial information: NCT02605265.