A. Amadori

A. Pavan

E. Zulato

F. Calabrese

G. Nardo

G. Pasello

G. Zago

I. Attili

L. Bonanno

L. Pasqualini

M. Fassan

M. Verza

P. Del Bianco

P.F. Conte

S. Frega

S. Indraccolo

V. Guarneri

English

Open Access Repository

1830O Liquid biopsy as tool to monitor and predict clinical benefit fromchemotherapy (CT) and immunotherapy (IT) in advanced non-smallcell lung cancer (aNSCLC): A prospective studyL. Bonanno1, E. Zulato2, I. Attili3, A. Pavan3, P. Del Bianco4, G. Nardo2, M. Verza2,L. Pasqualini2, G. Pasello1, G. Zago1, S. Frega3, M. Fassan5, F. Calabrese6, A. Amadori2,V. Guarneri3, P.F. Conte7, S. Indraccolo21Medical Oncology 2, Istituto Oncologico Veneto IRCCS, Padua, Italy, 2Immunology andMolecular Oncology, Istituto Oncologico Veneto IRCCS, Padua, Italy, 3Department ofSurgery, Oncology and Gastroenterology, University of Padua, Istituto OncologicoVeneto IRCCS, Padua, Italy, 4Clinical Trial and Biostatistics Unit, Istituto OncologicoVeneto IRCCS, Padua, Italy, 5Surgical Pathology Unit, Department of Medicine (DIMED),University-Hospital of Padua, Padua, Italy, 6Department of Cardiothoracic and VascularSciences, University of Padova, Padua, Italy, 7Surgery, Oncology and Gastroenterology,University of Padova, Istituto Oncologico Veneto IRCCS, Padua, ItalyBackground: Detecting tumor-specific genetic alterations in plasma has the potentialto monitor biological effects of treatment. Aim of the study is to validate the method inEGFR-ALK-ROS1 wild-type (wt) aNSCLC and explore the correlation of variation ofmutations in plasma with outcome.Methods: aNSCLC patients (pts) undergoing systemic anti-cancer treatment were pro-spectively enrolled in mono-institutional trial MAGIC-1. Tumor DNA was screenedthrough Mass Array (Sequenom) or Next-generation sequencing (NGS). Plasma sam-ples were collected at baseline (T1), after the first cycle of treatment (T2), at first radio-logical restaging (T3) and at radiological progression (PD) (T4). Plasma DNA wasanalyzed with Digital droplet PCR (ddPCR) for KRAS-mutated pts (KRAS-m) andNGS for KRAS-wt pts. Semiquantitative index of fractional abundancy (FA) of mutatedallele was used.Results: During 2017 we enrolled 161 pts. Here we depict the KRAS-m cohort (n¼ 43),including 11 pts treated with IT. At baseline, KRAS mutation (mut) in cfDNA wasdetected in 21 samples (49%; 95% CI 33.3-64.5). The predictive value of KRAS mutpresence in plasma increased from T1 to T3 and was statistically significant for PD(detected in 18 pts) at T3 with an AUC 0.73 (95% CI 0.55-0.91, p-value¼0.0132); sensi-tivity and specificity for PD at cut-off value of 0.013 FA were 58% (95% CI 28-85) and89% (95% CI 67-99). Any FA reduction (T1-T3) showed an ability to discriminatebetween groups (non-PD vs PD) of 85% (95% CI: 72-97, p-value<0.0001) with a sensi-tivity for detection of non-PD of 67% (95% CI 35-90) and a specificity of 89% (95% CI67-99). Among pts treated with IT, the predictive value of FA reduction (T1-T3) was86% (95% CI 58-100, p-value¼0.0124), with sensitivity of 100% (95% CI 16-100) andspecificity of 86% (95% CI 42-100). The only case treated with IT experiencing deathwithin 12 weeks had FA increase from 0 to 10% at T2.Conclusions: Dynamic variations of KRAS mut in plasma significantly correlate withradiological disease control. Early variation of FA of mutated allele potentially individ-uates pts experiencing worse outcome during IT. Plasma NGS analyses and expansioncohort in pts treated with IT are ongoing.Legal entity responsible for the study: Istituto Oncologico Veneto.Funding: Has not received any funding.Disclosure: All authors have declared no conflicts of interest.1831PD Molecular differences between colorectal cancers with mutations inhistone modifiers genes vs wild-type (WT) tumorsA. Puccini1, K. Poorman2, R. Goldberg3, A.F. Shields4, M. Winerip2, W.M. Korn5,M.D. Berger6, R. Tokunaga6, M. Naseem6, F. Battaglin6, W. Zhang6, S. Soni6, J.J. Hwang7,P. Philip4, J.L. Marshall8, H-J. Lenz61Medical Oncology 1, IRCCS AOU San Martino - IST - Istituto Nazionale per la Ricercasul Cancro, Genoa, Italy, 2Molecular Biology, Caris Life Sciences, Phoenix, AZ, USA,3Medical Oncology, West Virginia University Cancer Institute, Morgantown, WV, USA,4Medical Oncology, Karmanos Cancer Institute, Detroit, MI, USA, 5Molecular Biology,Caris Life Sciences, Phoenix, AZ, USA, 6Medical Oncology, University of SouthernCalifornia Norris Comprehensive Cancer Center, Los Angeles, CA, USA, 7Hematology/Medical Oncology, Levine Cancer Institute, Carolinas HealthCare System, Charlotte, NC,USA, 8Lombardi Cancer Center, Georgetown University Hospital, Washington DC, USABackground: Disruption of epigenetic regulation in CRC, particularly aberrant histonemethylation, has been shown to correlate with poorer survival rates in mCRC. Weaimed to highlight the molecular differences between CRC harboring pathologicalmutations in genes involved in histone modification (KMT family).Methods: Tumors were examined by NextGen sequencing, protein expression, andgene amplification. Tumor mutational burden (TMB) was calculated based on somaticmissense mutations (TMB-high 17 mt/MB) and microsatellite instability (MSI) wasevaluated on known MSI loci in the target regions. Chi-square and t-tests were used forcomparative analyses.Results: In total, 3621 CRC were examined, and 224 (6.2%) showed a pathologicalmutation in KMT2A, KMT2C, or KMT2D. Demographics were as follow: F/M 47%/53%, median age 60. KMT mutations were strongly associated with MSI-H (66.5% vs2.5%, P<.0001), TMB-high (72% vs 3%, P<.0001), BRAF mutation (24.7% vs 7.5%,P<.0001), PD-L1 overexpression (14.2% vs 2.7%, P<.0001), right-sided (11.7% vs3.4% in left-sided tumors, P¼ 0.001) and POLE mutations (6.7% vs 0.1%, P<.0001).Furthermore, the rate of mutations among several genes such as ATM, ATRX, BRCA1/2, MLH1, MSH2/6, PMS2 (all P< 0.001) were more frequently seen in the KMTmutated tumors. All remained significant after multiple test correction. When we ana-lyzed MSS tumors and POLE non-mutant tumors excluding MSI-H or POLE muta-tion, TMB-H remains more frequent in tumors with KMT mutations (8.3% vs 0.9%,P¼ 0.004), as well as several genes were more frequently mutated in KMT mutatedtumors compared to WT tumors (CDC73, 1.7% vs 0.0%, P¼.003; KDR, 1.7% vs0.03%, P¼.011; SDHB, 1.7% vs 0.1%, P¼.023; PRKDC, 1.7% vs. 0.1%, P¼.046;CHEK2, 5.6% vs 1.4%, P¼.049).Conclusions: Our findings provide the first exploratory data on KMT genes mutationsand their association with clinical and molecular features in CRC, in a large populationof patients. Further investigations are warranted to elucidate the association betweenTMB-H and histone modifications, potentially leading to a better understanding of epi-genetic alterations in CRC and to identify novel targets for therapeutic options for CRCpatients.Legal entity responsible for the study: Heinz-Josef Lenz.Funding: Has not received any funding.Disclosure: K. Poorman, M. Winerip, W.M. Korn: Employee: Caris Life Sciences.J.L. Marshall: Consultant: Caris Life Sciences. All other authors have declared noconflicts of interest.1832PD Phase I study of CC-90011 in patients with advanced solid tumorsand relapsed/refractory non-Hodgkin lymphoma (R/R NHL)A. Hollebecque1, J. de Bono2, R. Plummer3, N. Isambert4, P. Martin-Romano1,E. Baudin1, S. Mora5, A. Harding6, A. Nguyen7, E. Filvaroff7, M. Lamba8, K. Liu9, J. DeAlvaro10, J. DiMartino7, M. Zuraek11, Z. Nikolova51Drug Development Department (DITEP), Institut Gustave Roussy, Villejuif, France,2Division of Clinical Studies, The Institute of Cancer Research and Royal Marsden,London, UK, 3Newcastle University, Northern Institute for Cancer Research, Newcastle,UK, 4Unité de Phases Précoces U2P – CLIP2 BFC, Centre Georges-François Leclerc (Dijon),Dijon, France, 5Translational Development, Celgene Institute Translational ResearchEurope-CITRE, Seville, Spain, 6Translational Development, Celgene Ltd, London, UK,7Epigenetics, Celgene Corporation, South San Francisco, CA, USA, 8TranslationalDevelopment, Celgene Corporation, Summit, NJ, USA, 9Biostatistics, CelgeneCorporation, Berkeley Heights, USA, 10Hematology, Celgene Institute TranslationalResearch Europe-CITRE, Seville, Spain, 11Translational Medicine, Celgene Corporation,South San Francisco, CA, USABackground: CC-90011 is a selective, reversible inhibitor of the epigenetic target,lysine-specific demethylase 1A (LSD1) that has demonstrated anti-tumor activityagainst neuroendocrine cells in vitro and in xenograft models.Methods: This is a phase I, first-in-human clinical study of CC-90011 in patients (pts)with advanced unresectable solid tumors and R/R NHL. Pts received oral CC-90011once/week in 28-day cycles. Primary objectives were to determine safety, maximum-tolerated dose (MTD), and/or recommended phase II dose (RP2D). Secondary objec-tives were to measure preliminary efficacy, pharmacokinetics (PK), and pharmacody-namics (PD).Results: As of 15 Jan 2018, 35 pts were enrolled; 34 with advanced solid tumors, includ-ing 17 with neuroendocrine tumors (NETs) and 1 with R/R NHL. They received esca-lating doses of CC-90011 at 1.25 mg (n¼ 4), 2.5 mg (n¼ 5), 5 mg (n¼ 6), 10 mg(n¼ 4), 20 mg (n¼ 4), 40 mg (n¼ 6), or 80 mg (n¼ 4). The MTD and RP2D have notyet been established. The median age was 61 y (range, 22-75), 19 (54%) were male, with2 (range, 1-4) median number of prior systemic anticancer therapies. No dose-limitingtoxicities were reported. The only treatment-related grade 3/4 adverse event (AE) wasthrombocytopenia (9%). Serious AEs occurred in 24% of pts; none were treatment-related. Peak plasma concentrations were 2-4 hours post-dose and terminal eliminationhalf-life was approximately 64 hours; increase in plasma exposures was dose propor-tional. Blood biomarker analyses showed increasing suppression of MMD and MYL9expression with higher CC-90011 doses suggesting target engagement at doses40 mg. Overall, 13 (39%) pts had stable disease (SD). Prolonged SD (4 mo) wasobserved in 5 pts with solid tumors; notably, 3 of those pts had bronchial NETs [5 mgVC European Society for Medical Oncology 2018. Published by Oxford University Press on behalf of the European Society for Medical Oncology.All rights reserved. For permissions, please email: journals.permissions@oup.com.Annals of Oncology 29 (Supplement 8): viii649–viii669, 2018doi:10.1093/annonc/mdy303TRANSLATIONAL RESEARCHDownloaded from https://academic.oup.com/annonc/article-abstract/29/suppl_8/mdy303/5140800 by guest on 03 May 2019

liquid biopsy as tool to monitor and predict clinical benefit from chemotherapy ct and immunotherapy it in advanced non small cell lung cancer ansclc a prospective study

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liquid biopsy as tool to monitor and predict clinical benefit from chemotherapy ct and immunotherapy it in advanced non small cell lung cancer ansclc a prospective study

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