- Email: [email protected]
Prospective pathological experience with research biopsies in the context of clinical trials at Vall d’Hebron Institute of Oncology
abstracts
Annals of Oncology 1883P
Is there a role for next-generation sequencing (NGS) profiling on metastatic non-colorectal gastrointestinal carcinomas (MNCGIC) in developing countries? A single center experience
M.F.S.A. Ribeiro1, L.L. Gadotti1, C. Godoy1, A.A.L. Pereira2, D. de Freitas1, M. Crosara2, L. Dib2, F.P. Costa1, F.C. Capareli1, D.L.F. Jardim1, B. Gumz2, G.S. Fernandes2 1 Oncology Center, Hospital Sırio-Liban^es, Sao Paulo, Brazil, 2Oncology Center, Hospital Sırio-Liban^es, Brasılia, Brazil
Medicine. B. Gumz: Honoraria (self): Novartis. All other authors have declared no conflicts of interest.
1884P
Metastatic cancer whole-exome sequencing in daily practice
M. Re´da1, C. Richard2, J. Niogret1, J-D. Fumet1, A. Bertaut3, J. Blanc3, C. Truntzer2, I. Desmoulins1, S. Ladoire1, L. Bengrine-Lefevre1, N. Isambert1, A. Hervieu1, C. Lepage4, P. Foucher5, C. Borg6, L. Arnould7, S. Nambot8, L. Faivre8, R. Boidot7, F. Ghiringhelli1 1 Department of Medical Oncology, Centre Georges-Franc¸ois Leclerc, Dijon, France, 2 Platform of Transfer in Cancer Biology, Centre Georges-Franc¸ois Leclerc, Dijon, France, 3 Biostatistics and Data Management, Centre Georges-Franc¸ois Leclerc, Dijon, France, 4 Gastro-enterology, CHU Dijon, Dijon, France, 5Thoracic Oncology, CHU Le Bocage (Dijon), Dijon, France, 6Department of Medical Oncology, CHU Besanc¸on, Hoˆpital Jean Minjoz, Besanc¸on, France, 7Department of Biology and Tumor Pathology, Centre Georges-Franc¸ois Leclerc, Dijon, France, 8Department of Genetics, CHU Dijon, Dijon, France Background: Genomically-guided clinical trials began to evaluate the efficacy of molecularly-targeted therapies across different tumor types sharing genetic mutations, but trial organisation remains complex. Here we address the feasibility and utility of routine somatic and constitutional exome analysis in a prospective cohort of metastatic cancer patients. Methods: Exoma trial is a multicenter, prospective clinical trial to test whether exome analysis is feasible and improves access to targeted therapies in routine care. Eligible patients presented a metastatic cancer progressing after at least one line of systemic therapy. Constitutional genetics testing required geneticist consultation. Somatic and constitutive exome analysis was restricted to 342 genes adapted from Foundation Medicine gene list. Variants were classified using Tier models and molecular tumor board made therapeutic recommendations based on ESMO guidelines. Primary endpoint was PFS2/PFS1 ratio. Results: Between May 2016 and October 2018, 506 patients were included. The main tumor type was breast cancer, followed by colorectal and pancreatic cancer. Median time required for tumor sample reception was 8 days. Median time from sample reception to results was 52 days. Somatic analysis was performed for 456 patients (90.1%). Both somatic and constitutional analyses were performed for 386 patients (76.3%). The most frequently altered gene was TP53 (38.6%), followed by KRAS (18%) and PIK3CA (13.8%). In total, 342 patients (67.5%) received a therapeutic proposal, including change in chemotherapy or addition of an antiangiogenic drug. 79 patients (15.6%) were treated with NGS matched therapy (PIK3/mTOR inhibitors (27.8%), PARP inhibitors (24%), tyrosine kinase inhibitors (21.5%) or immunotherapy
Volume 30 | Supplement 5 | October 2019
1885P
Genomic-guided individualized precision therapy in refractory metastatic solid tumor patients with extensively poor performance status: A Chinese single institutional prospective observational realworld study
H. Wang Department of Medical Oncology, The Second Hospital of Tianjin Medical University, Tianjin, China Background: In recent years, molecular interrogation of tumors and deployment of matched individualized precision therapies has shown remarkable responses in a variety of refractory malignancies. However, to date, few prospective studies have evaluated comprehensive next-generation sequencing (NGS) testing for actionable genomic alterations to guide matched therapy in advanced refractory solid tumors with extensively poor performance status. Methods: The study was a prospective, observational mono-institutional study. The main eligibility criteria were that patients diagnosed with treatment-refractory disease with poor performance status (ECOG PS 3) undergoing commercial NGS (Foundation Medicine) testing with the intent of clinical application of available matched targeted agents. Variants were classified in three levels of actionability using a novel scale tool. Treatment recommendations were discussed in a molecular tumor board. Among these treated patients, the primary end point for the analysis was the ORR. Secondary end points included DCR, PFS, OS and safety. The registry is ongoing. Results: From October 2018 to April 2019, 48 patients were enrolled, which concluded ovarian cancer, stomach cancer, liver cancer, and so on, all underwent NGS of a metastatic site biopsy. About 93.8 percent of patients underwent successful molecular analysis (93.8%) and treatment recommendations were given to 28 patients (62.2 %). These included single-agent targeted therapies (60.7%), checkpoint inhibitors (25%), and combination targeted therapies (14.3%). Treatment recommendations were implemented in 22 of 28 patients (78.6%), of whom 8 (36.4%) showed complete remission (n ¼ 1) or partial response (n ¼ 7), in addition, 16 patients (72.7%) receiving off-label treatments. Conclusions: Genomic-guided individualized precision therapy is effective for a small proportion of patients in challenging clinical situations. Molecular tumor board and evidenced based actionable gene variation scale tool are effective approach to improve the effectiveness of genomic-guided precision therapy. Legal entity responsible for the study: Institutional review board of the Second Hospital of Tianjin Medical University. Funding: Has not received any funding. Disclosure: The author has declared no conflicts of interest.
1886P
Prospective pathological experience with research biopsies in the context of clinical trials at Vall d’Hebron Institute of Oncology
P.G. Nuciforo1, J. Jimenez1, R. Fasani1, F. Ruiz2, C. Sevillano1, G. Sanchez1, P. Martinez1, noz-Couselo4, X. Serres3, C. Saura4, E. Elez4, E. Felip4, A. Oaknin4, I. Brana4, E. Mu~ T. Macarulla Mercade4, M. Alsina Maqueda4, J. Carles4, R. Dienstmann2, J. Tabernero4, E. Garralda4 1 Molecular Oncology Group, Vall dHebron Institute of Oncology (VHIO)-Cellex Center, Barcelona, Spain, 2Oncology Data Science (Odyssey) Group, Vall d’Hebron University Hospital, Barcelona, Spain, 3Radiology, Vall d’Hebron University Hospital, Barcelona, Spain, 4Oncology, Vall d’Hebron University Hospital and Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain Background: In the recent years, there has been an increased incorporation of research biopsies in clinical trials and translational research. However, limited information is available on the determinants of sample quality, which could help identifying parameters for successful biopsy ascertainment. Methods: Data from all consecutive patients who had one or more research biopsies at our institution as part of a phase I-III trials and/or translational research projects approved by Ethics Committee from January 2017 to December 2018 were extracted and analyzed. Results: A total of 1517 procedures were performed in 979 consenting patients, reaching in total 3811 tissue samples (71% at screening and 29% on-treatment or at progression) with an average of 2.5 samples per procedure. Tumor biopsies were obtained
doi:10.1093/annonc/mdz268 | v765
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz268.013/5576315 by guest on 26 October 2019
Background: Metastatic non-colorectal cancers have adverse prognosis and no target or immunotherapy is approved until now. NGS platforms are supposed to be useful tailoring systemic treatments and/or screening patients(pts) for early phase clinical trials. Although attractive, NGS-tailored therapies (NGS-TT) can have disappointing results in not approved indications outside clinical trials. In this analysis we evaluated the tumor genetic profiles including potential germline mutations, suggested therapies, available clinical trials, and the results for off-label NGS-TT. Methods: we performed a retrospective assessment of clinical and molecular characteristics, NGS-TT prescribed and responses in a cohort of MNCGIC evaluated through the 315 genes NGS platform between 2013-2019. We looked for potential germline mutations in mismatch-repair genes and BRCA1/2, as well as the TP53R337H founder mutation. Results: among 78 pts, the median age was 58.5y (20-79), with 51 (65%) males and 27 (35%) females. The most common sites were pancreas (41%), stomach (15.4%) and biliary tract (15,4%); 83% were ECOG 0/1, with up to 2 lines of therapy (60.25%). Mean number of altered genes was 4.41 (1-19) and tumor mutational burden (TMB) was assessed in 24 pts, with 79% TMB-low (mean 5.22 muts/Mb). Ten pts (12.85%) underwent off-label NGS-TT after discussion at multidisciplinary tumor boards; among 9 available for response evaluation, 7 experienced progression as best response. Clinical trials were suggested for 73 pts (93,6%), but only one patient (pt) was referred to it, since all trials where abroad. We also identified 3 cases for which germline sequencing would be of value (1 pt with TP53 R337H mutation; 2 young gastric cancer pts: one with concurrent MSH6/BRCA2 mutations and another with MLH1truncation exon10 alteration). Conclusions: in our cohort, the adoption of NGS to tailor systemic treatment did not show an important impact for MNCGIC pts. Increase participation of developing country centers in clinical trials is strongly needed. Potentially germline mutations were present in this series and deserve further investigation. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: D. de Freitas: Honoraria (self): Roche. D.L.F. Jardim: Honoraria (self): Foundation
(11.4%)). Data for both PFS2 and PFS1 were available for 148 patients (29.2%). PFS2/ PFS1 ratio was > 1,3 for 23,5% of patients treated with the NGS matched therapy (n ¼ 51) and 23,7% of patients treated with standard therapy (n ¼ 97). Conclusions: Study shows that exome analysis is feasible in cancer routine care, improves detection of genetic predispositions and enhances access to target therapies. However, no differences were observed between PFS ratios of patients treated with matched therapy versus standard. Clinical trial identification: NCT02840604. Legal entity responsible for the study: Franc¸ois Ghiringhelli. Funding: Centre Georges-Franc¸ois Leclerc. Disclosure: All authors have declared no conflicts of interest.
abstracts
MSD. C. Saura: Advisory / Consultancy: AstraZeneca, Celgene, Daiichi Sankyo, Eisai, Roche, Genomic health, Novartis, Pfizer, Pierre Fabre, Puma, Synthon and Sanofi; Travel / Accommodation / Expenses: AstraZeneca, Celgene, Daiichi Sankyo, Eisai, Roche, Genomic health, Novartis, Pfizer, Pierre Fabre, Puma, Synthon and Sanofi. E. Elez: Honoraria (self): Hoffman La-Roche, Bristol Myers Squibb, Servier, Amgen, Merck Serono, Array, Sanofi; Advisory / Consultancy: Hoffman La-Roche, Bristol Myers Squibb, Servier, Amgen, Merck Serono, Array, Sanofi; Research grant / Funding (self): Hoffman La-Roche, Bristol Myers Squibb, Servier, Amgen, Merck Serono, Array, Sanofi; Honoraria (institution): Array, MSD, Abbvie, Amgen, GSK, AstraZeneca, Bristol Myers Squibb, Novartis, Boehringer, Ingelheim, Hoffman La-Roche.. E. Felip: Speaker Bureau / Expert testimony: AbbVie, AstraZeneca, Blueprint medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Guardant Health, Janssen, Medscape, Merck KGaA, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Takeda, Touchtime.; Advisory / Consultancy: AbbVie, AstraZeneca, Blueprint medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Guardant Health, Janssen, Medscape, Merck KGaA, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Takeda, Touchtime.; Research grant / Funding (institution): Fundaci on Merck Salud, Grant for Oncology Innovation EMD Serono. A. Oaknin: Advisory / Consultancy: Roche, AstraZeneca, PharmaMar, Clovis Oncology, Tesaro, Inmunogen and Genmab; Travel / Accommodation / Expenses: Roche, AstraZeneca, and PharmaMar. E. Mu~ noz-Couselo: Advisory / Consultancy: Amgen, Bristol-Myers Squibb, Merck, Sharp & Dohme, Novartis, Pierre Fabre, and Roche; Honoraria (self): Amgen, Bristol-Myers Squibb, Merck, Sharp & Dohme, Novartis, Pierre Fabre, Sanofi and Roche ; Leadership role, Clinical trial participation (principal investigator): Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Merck, Sharp & Dohme, Novartis, Pierre Fabre, and Roche. T. Macarulla Mercade: Advisory / Consultancy: Shire Pharmaceuticals, Roche, Tesaro, Batxer, Sanofi, Celgene, QED Therapeutics, Genzyme Europe, Baxalta, Bayer, Incyte, Genzyme ; Travel / Accommodation / Expenses: from Merck, H3 Biomedicine, Bayer, Sanofi. M. Alsina Maqueda: Advisory / Consultancy: Servier, Lilly, BMS and MS. Honoraria for speaking issues from Servier, BMS, MSD, Lilly, Roche and Amge; Travel / Accommodation / Expenses: Servier, Roche, Amgen and Lilly. J. Carles: Advisory / Consultancy: Bayer / Johnson & Johnson / Bristol-Myers Squibb / Astellas Pharma / Pfizer / Sanofi / MSD Oncology / Roche/ AstraZe´neca; Speaker Bureau / Expert testimony: Bayer / Johnson & Johnson / Asofarma / Astellas Pharma; Research grant / Funding (institution): AB Science, Aragon Pharmaceuticals, Arog Pharmaceuticals, INC, Astellas Pharma., AstraZeneca AB, Aveo Pharmaceuticals INC, Bayer AG, Blueprint Medicines Corporation, BN Immunotherapeutics INC, Boehringer Ingelheim Espa~ na, S.A., Bristol-Myers Squibb Inter. R. Dienstmann: Advisory / Consultancy: Roche; Research grant / Funding (self): Merck. J. Tabernero: Advisory / Consultancy: Array Biopharma, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Chugai, Genentech, Inc., Genmab A/S, Halozyme, Imugene Limited, Inflection Biosciences Limited, Ipsen, Kura Oncology, Lilly, MSD, Menarini, Merck Serono, Merrimack, Merus, Molecular Part. E. Garralda: Advisory / Consultancy: F.Hoffmann-La Roche, Ellipses Pharma, Neomed Therapeutics1 Inc, Boehringer Ingelheim, Janssen Global Services, ; Speaker Bureau / Expert testimony: BristolMayers Squibb ; Travel / Accommodation / Expenses: Merck Sharp & Dohme, Glycotope, Menarini; Research grant / Funding (self), Scitron Project - VHIO Technology : Novartis; Research grant / Funding (institution), Clinical Trial Principal Investigator: Principia Biopharma Inc, Lilly, S.A, Novartis, Genentech, Loxo Oncologi Inc, F.Hoffmann-La Roche Ltd, Symphogen A/S, Merck, Sharp & Dohme de Espa~ na, S.A, Incyte Biosciences International, Pharma Mar, S.A.U, Kura Oncology Inc, Macrogenics Inc, Glycotope G; Leadership role: ESMO Women for Oncology - W4O. All other authors have declared no conflicts of interest.
1887P
Development of a comprehensive next-generation targeted sequencing assay for detection of gene-fusions in solid tumors
V.K. Mittal1, S.P. Myrand1, D. Cyanam1, P.D. Williams1, G.G. Bee2, A. Marcovitz3, R. Gottimukkala3, F. Hyland4, C. Allen5, E. Wong-Ho3, S. Sadis1, C. Van Loy2, J. Kilzer2, N. Khazanov1 1 Clinical Sequencing Division, Thermo Fisher Scientific, Ann Arbor, MI, USA, 2Clinical Sequencing Division, Thermo Fisher Scientific, Carlsbad, CA, USA, 3Clinical Sequencing Division, Thermo Fisher Scientific, South San Francisco, CA, USA, 4CSD, Thermo Fisher Scientific, San Francisco, USA, 5Field Applications, Thermo Fisher Scientific, Paisley, UK Background: Gene fusions caused by chromosomal rearrangements play an important role in oncogenesis, the progression of cancer and the selection of targeted therapies. Next-generation sequencing (NGS) using RNA enables sensitive, specific and precise detection of potentially clinically relevant gene fusions, especially when the fusion breakpoint is known. We have developed an NGS solution appropriate for FFPE tissues to detect fusion biomarkers in routine clinical research. Methods: Fusion content was selected based on prioritization of actionability, verified fusion isoforms reported in the literature and collaborations, as well as prevalence of solid tumor fusion driver genes. The assay was designed to use Ion AmpliSeq multiplex
v766 | Translational Research
PCR chemistry using manual or automated library preparation, automated templating on the Ion Chef, and sequencing on the Ion Torrent GeneStudioTM S5 sequencing platform. The analysis was supported by fully automated analysis software that performs sample QC, read-filtering, fusion calling and reporting. Streamlined access to decision support software was enabled by OncomineTM Reporter. Results: Over 1200 targeted isoforms from over 50 known fusion driver genes were incorporated into the assay that included prominent fusion drivers such as ALK, RET, ROS1, NTRK1/2/3 and FGFR1/2/3, and intragenic fusion events in MET, EGFR, BRAF and AR. The assay also reported non-targeted fusion events in relevant driver genes by using a novel statistically significant expression imbalance algorithm comparing 5’and 3’- end gene expression. A preliminary development study was performed using commercially available total RNA for a Tri-Fusion control and SeraseqTM Fusion RNA Mix v3 where all of the expected fusions were detected with 100% sensitivity and specificity. Results were also concordant when characterized FFPE tumor samples with known fusion targets were tested using the assay. Conclusions: A comprehensive NGS assay was developed to support clinical research in oncology for detecting relevant RNA structural alterations from solid tumor FFPEs. An update on assay performance will be presented. Legal entity responsible for the study: Thermo Fisher Scientific. Funding: Has not received any funding. Disclosure: V.K. Mittal: Shareholder / Stockholder / Stock options, Full / Part-time employment: Thermo Fisher Scientific. S.P. Myrand: Shareholder / Stockholder / Stock options, Full / Part-time employment: Thermo Fisher Scientific. D. Cyanam: Shareholder / Stockholder / Stock options, Full / Part-time employment: Thermo Fisher Scientific. P.D. Williams: Shareholder / Stockholder / Stock options, Full / Part-time employment: Thermo Fisher Scientific. G.G. Bee: Shareholder / Stockholder / Stock options, Full / Part-time employment: Thermo Fisher Scientific. A. Marcovitz: Shareholder / Stockholder / Stock options, Full / Part-time employment: Thermo Fisher Scientific. R. Gottimukkala: Shareholder / Stockholder / Stock options, Full / Part-time employment: Thermo Fisher Scientific. F. Hyland: Shareholder / Stockholder / Stock options, Full / Part-time employment: Thermo Fisher Scientific. C. Allen: Shareholder / Stockholder / Stock options, Full / Part-time employment: Thermo Fisher Scientific. E. Wong-Ho: Shareholder / Stockholder / Stock options, Full / Part-time employment: Thermo Fisher Scientific. S. Sadis: Shareholder / Stockholder / Stock options, Full / Part-time employment: Thermo Fisher Scientific. C. Van Loy: Shareholder / Stockholder / Stock options, Full / Part-time employment: Thermo Fisher Scientific. J. Kilzer: Shareholder / Stockholder / Stock options, Full / Part-time employment: Thermo Fisher Scientific. N. Khazanov: Shareholder / Stockholder / Stock options, Full / Part-time employment: Thermo Fisher Scientific.
1888P
Next-generation sequencing for better treatment strategy of cancer of unknown primary (CUP)
K.K. Lee1, M. Kim2, K-M. Kim3, S.T. Kim4, J. Lee4, S.J. Lee5 Hemato-Oncology, Dongsan Medical Center Kemyung University Hospital, Daegu, Republic of Korea, 2Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Republic of Korea, 3Pathology, Samsung Medical Center, Seoul, Republic of Korea, 4Medicine, Samsung Medical Center, Seoul, Republic of Korea, 5Internal Medicine, EWHA Womans University Seoul Hospital, Seoul, Republic of Korea
1
Background: Cancer of unknown primary (CUP) consists of diverse histology types of cancer and have shown poor prognosis. In the era of precision medicine, next-generation sequencing (NGS) may contribute new therapeutic target which could improve treatment outcomes of CUP. Methods: Patients who were diagnosed with CUP and underwent NGS exam between August 2017 and August 2018 at Samsung medical center were included for the study. NGS data were analyzed, and medical records were reviewed retrospectively to evaluate clinical characteristics and response to various treatments. Results: A total of 21 patients with CUP who had NGS data were analyzed. The median age was 58 (range, 35-78 years). Male was dominant (57.1%) and most of the patients were ECOG 1 (90.5%). Among the patients, 14 (66.7%) were poorly differentiated carcinoma, 6 (28.6%) patients were adenocarcinoma, and one patient was squamous cell carcinoma. Most common metastatic site was lymph node (57.1%), followed by bone (38.1%), lung (19.0%), pleura (19.0%). Paclitaxel combined with carboplatin was most frequently used regimen for the first-line treatment (57.1%). Cisplatin-based chemotherapy was used second most (28.6%). One patient showed complete remission during the first-line treatment whereas 7 patients and 5 patients achieved the best response of partial response and stable disease, respectively. Median progression-free survival was 4 months (95% CI: 0.316-7.684), and median overall survival was not reached. Except four patients, 17 (81.0%) patients showed 25 gene alterations on the NGS results. TP53 mutation was observed most commonly (n ¼ 6, 25.6%), followed by ERBB2 alterations (n ¼ 3, mutations [n ¼ 2], amplification [n ¼ 1]), KRAS mutation (n ¼ 2), MET amplification (n ¼ 2), CDKN2A deletion (n ¼ 2), and MYC amplification (n ¼ 2). One patient harbored ERBB2 amplification was treated with trastuzumab combined with paclitaxel, and the patient demonstrated sustained partial response at 9 months, until the data cut-off date. Conclusions: Most of CUP patients had variety actionable gene alterations. Precision medicine based on molecular analysis with NGS will improve the prognosis of the patients with CUP. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
Volume 30 | Supplement 5 | October 2019
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz268.013/5576315 by guest on 26 October 2019
under ultrasound (60%), computed tomography (12%) guidance or non-guided (28%). Samples were formalin-fixed and paraffin embedded (FFPE, 48%), snap frozen (20%) or alternatively stabilized (32%) according to study protocol. Tumor content (TC) was determined in 1514 FFPE samples: 90% of them had tumor cells, 81% showed more than 10% TC and 59% more than 50% TC. No significant difference in TC was found between screening and on-treatment biopsies (p ¼ 0.12). Sample quality was negatively affected by biopsy site (<10% TC rates in non-visceral vs visceral were 26% vs 14%, respectively, p<.0001), method (non-guided vs guided, 37% vs 17%, p<.0001), and operator expertise (<50 vs > 50 biopsies x year, 31% vs 16.5%, p<.0001). In a multivariate logistic model, biopsy site and method were independent determinants of poor sample quality (<10% TC). Within the same biopsy procedure, inter-sample variability was low with 77% of samples showing between 0% to 30% difference in TC. Among 134 intra-trial sequential biopsies with available TC assessment, only 25% pairs were not suitable for performing downstream comparative analyses (<10% TC). Conclusions: Our experience provides important information to improve research biopsy effectiveness in a biomarker program linked to clinical trials. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: P.G. Nuciforo: Honoraria (self): Bayer; Honoraria (self): Novartis; Honoraria (self):
Annals of Oncology
Annals of Oncology 1883P
Is there a role for next-generation sequencing (NGS) profiling on metastatic non-colorectal gastrointestinal carcinomas (MNCGIC) in developing countries? A single center experience
M.F.S.A. Ribeiro1, L.L. Gadotti1, C. Godoy1, A.A.L. Pereira2, D. de Freitas1, M. Crosara2, L. Dib2, F.P. Costa1, F.C. Capareli1, D.L.F. Jardim1, B. Gumz2, G.S. Fernandes2 1 Oncology Center, Hospital Sırio-Liban^es, Sao Paulo, Brazil, 2Oncology Center, Hospital Sırio-Liban^es, Brasılia, Brazil
Medicine. B. Gumz: Honoraria (self): Novartis. All other authors have declared no conflicts of interest.
1884P
Metastatic cancer whole-exome sequencing in daily practice
M. Re´da1, C. Richard2, J. Niogret1, J-D. Fumet1, A. Bertaut3, J. Blanc3, C. Truntzer2, I. Desmoulins1, S. Ladoire1, L. Bengrine-Lefevre1, N. Isambert1, A. Hervieu1, C. Lepage4, P. Foucher5, C. Borg6, L. Arnould7, S. Nambot8, L. Faivre8, R. Boidot7, F. Ghiringhelli1 1 Department of Medical Oncology, Centre Georges-Franc¸ois Leclerc, Dijon, France, 2 Platform of Transfer in Cancer Biology, Centre Georges-Franc¸ois Leclerc, Dijon, France, 3 Biostatistics and Data Management, Centre Georges-Franc¸ois Leclerc, Dijon, France, 4 Gastro-enterology, CHU Dijon, Dijon, France, 5Thoracic Oncology, CHU Le Bocage (Dijon), Dijon, France, 6Department of Medical Oncology, CHU Besanc¸on, Hoˆpital Jean Minjoz, Besanc¸on, France, 7Department of Biology and Tumor Pathology, Centre Georges-Franc¸ois Leclerc, Dijon, France, 8Department of Genetics, CHU Dijon, Dijon, France Background: Genomically-guided clinical trials began to evaluate the efficacy of molecularly-targeted therapies across different tumor types sharing genetic mutations, but trial organisation remains complex. Here we address the feasibility and utility of routine somatic and constitutional exome analysis in a prospective cohort of metastatic cancer patients. Methods: Exoma trial is a multicenter, prospective clinical trial to test whether exome analysis is feasible and improves access to targeted therapies in routine care. Eligible patients presented a metastatic cancer progressing after at least one line of systemic therapy. Constitutional genetics testing required geneticist consultation. Somatic and constitutive exome analysis was restricted to 342 genes adapted from Foundation Medicine gene list. Variants were classified using Tier models and molecular tumor board made therapeutic recommendations based on ESMO guidelines. Primary endpoint was PFS2/PFS1 ratio. Results: Between May 2016 and October 2018, 506 patients were included. The main tumor type was breast cancer, followed by colorectal and pancreatic cancer. Median time required for tumor sample reception was 8 days. Median time from sample reception to results was 52 days. Somatic analysis was performed for 456 patients (90.1%). Both somatic and constitutional analyses were performed for 386 patients (76.3%). The most frequently altered gene was TP53 (38.6%), followed by KRAS (18%) and PIK3CA (13.8%). In total, 342 patients (67.5%) received a therapeutic proposal, including change in chemotherapy or addition of an antiangiogenic drug. 79 patients (15.6%) were treated with NGS matched therapy (PIK3/mTOR inhibitors (27.8%), PARP inhibitors (24%), tyrosine kinase inhibitors (21.5%) or immunotherapy
Volume 30 | Supplement 5 | October 2019
1885P
Genomic-guided individualized precision therapy in refractory metastatic solid tumor patients with extensively poor performance status: A Chinese single institutional prospective observational realworld study
H. Wang Department of Medical Oncology, The Second Hospital of Tianjin Medical University, Tianjin, China Background: In recent years, molecular interrogation of tumors and deployment of matched individualized precision therapies has shown remarkable responses in a variety of refractory malignancies. However, to date, few prospective studies have evaluated comprehensive next-generation sequencing (NGS) testing for actionable genomic alterations to guide matched therapy in advanced refractory solid tumors with extensively poor performance status. Methods: The study was a prospective, observational mono-institutional study. The main eligibility criteria were that patients diagnosed with treatment-refractory disease with poor performance status (ECOG PS 3) undergoing commercial NGS (Foundation Medicine) testing with the intent of clinical application of available matched targeted agents. Variants were classified in three levels of actionability using a novel scale tool. Treatment recommendations were discussed in a molecular tumor board. Among these treated patients, the primary end point for the analysis was the ORR. Secondary end points included DCR, PFS, OS and safety. The registry is ongoing. Results: From October 2018 to April 2019, 48 patients were enrolled, which concluded ovarian cancer, stomach cancer, liver cancer, and so on, all underwent NGS of a metastatic site biopsy. About 93.8 percent of patients underwent successful molecular analysis (93.8%) and treatment recommendations were given to 28 patients (62.2 %). These included single-agent targeted therapies (60.7%), checkpoint inhibitors (25%), and combination targeted therapies (14.3%). Treatment recommendations were implemented in 22 of 28 patients (78.6%), of whom 8 (36.4%) showed complete remission (n ¼ 1) or partial response (n ¼ 7), in addition, 16 patients (72.7%) receiving off-label treatments. Conclusions: Genomic-guided individualized precision therapy is effective for a small proportion of patients in challenging clinical situations. Molecular tumor board and evidenced based actionable gene variation scale tool are effective approach to improve the effectiveness of genomic-guided precision therapy. Legal entity responsible for the study: Institutional review board of the Second Hospital of Tianjin Medical University. Funding: Has not received any funding. Disclosure: The author has declared no conflicts of interest.
1886P
Prospective pathological experience with research biopsies in the context of clinical trials at Vall d’Hebron Institute of Oncology
P.G. Nuciforo1, J. Jimenez1, R. Fasani1, F. Ruiz2, C. Sevillano1, G. Sanchez1, P. Martinez1, noz-Couselo4, X. Serres3, C. Saura4, E. Elez4, E. Felip4, A. Oaknin4, I. Brana4, E. Mu~ T. Macarulla Mercade4, M. Alsina Maqueda4, J. Carles4, R. Dienstmann2, J. Tabernero4, E. Garralda4 1 Molecular Oncology Group, Vall dHebron Institute of Oncology (VHIO)-Cellex Center, Barcelona, Spain, 2Oncology Data Science (Odyssey) Group, Vall d’Hebron University Hospital, Barcelona, Spain, 3Radiology, Vall d’Hebron University Hospital, Barcelona, Spain, 4Oncology, Vall d’Hebron University Hospital and Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain Background: In the recent years, there has been an increased incorporation of research biopsies in clinical trials and translational research. However, limited information is available on the determinants of sample quality, which could help identifying parameters for successful biopsy ascertainment. Methods: Data from all consecutive patients who had one or more research biopsies at our institution as part of a phase I-III trials and/or translational research projects approved by Ethics Committee from January 2017 to December 2018 were extracted and analyzed. Results: A total of 1517 procedures were performed in 979 consenting patients, reaching in total 3811 tissue samples (71% at screening and 29% on-treatment or at progression) with an average of 2.5 samples per procedure. Tumor biopsies were obtained
doi:10.1093/annonc/mdz268 | v765
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz268.013/5576315 by guest on 26 October 2019
Background: Metastatic non-colorectal cancers have adverse prognosis and no target or immunotherapy is approved until now. NGS platforms are supposed to be useful tailoring systemic treatments and/or screening patients(pts) for early phase clinical trials. Although attractive, NGS-tailored therapies (NGS-TT) can have disappointing results in not approved indications outside clinical trials. In this analysis we evaluated the tumor genetic profiles including potential germline mutations, suggested therapies, available clinical trials, and the results for off-label NGS-TT. Methods: we performed a retrospective assessment of clinical and molecular characteristics, NGS-TT prescribed and responses in a cohort of MNCGIC evaluated through the 315 genes NGS platform between 2013-2019. We looked for potential germline mutations in mismatch-repair genes and BRCA1/2, as well as the TP53R337H founder mutation. Results: among 78 pts, the median age was 58.5y (20-79), with 51 (65%) males and 27 (35%) females. The most common sites were pancreas (41%), stomach (15.4%) and biliary tract (15,4%); 83% were ECOG 0/1, with up to 2 lines of therapy (60.25%). Mean number of altered genes was 4.41 (1-19) and tumor mutational burden (TMB) was assessed in 24 pts, with 79% TMB-low (mean 5.22 muts/Mb). Ten pts (12.85%) underwent off-label NGS-TT after discussion at multidisciplinary tumor boards; among 9 available for response evaluation, 7 experienced progression as best response. Clinical trials were suggested for 73 pts (93,6%), but only one patient (pt) was referred to it, since all trials where abroad. We also identified 3 cases for which germline sequencing would be of value (1 pt with TP53 R337H mutation; 2 young gastric cancer pts: one with concurrent MSH6/BRCA2 mutations and another with MLH1truncation exon10 alteration). Conclusions: in our cohort, the adoption of NGS to tailor systemic treatment did not show an important impact for MNCGIC pts. Increase participation of developing country centers in clinical trials is strongly needed. Potentially germline mutations were present in this series and deserve further investigation. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: D. de Freitas: Honoraria (self): Roche. D.L.F. Jardim: Honoraria (self): Foundation
(11.4%)). Data for both PFS2 and PFS1 were available for 148 patients (29.2%). PFS2/ PFS1 ratio was > 1,3 for 23,5% of patients treated with the NGS matched therapy (n ¼ 51) and 23,7% of patients treated with standard therapy (n ¼ 97). Conclusions: Study shows that exome analysis is feasible in cancer routine care, improves detection of genetic predispositions and enhances access to target therapies. However, no differences were observed between PFS ratios of patients treated with matched therapy versus standard. Clinical trial identification: NCT02840604. Legal entity responsible for the study: Franc¸ois Ghiringhelli. Funding: Centre Georges-Franc¸ois Leclerc. Disclosure: All authors have declared no conflicts of interest.
abstracts
MSD. C. Saura: Advisory / Consultancy: AstraZeneca, Celgene, Daiichi Sankyo, Eisai, Roche, Genomic health, Novartis, Pfizer, Pierre Fabre, Puma, Synthon and Sanofi; Travel / Accommodation / Expenses: AstraZeneca, Celgene, Daiichi Sankyo, Eisai, Roche, Genomic health, Novartis, Pfizer, Pierre Fabre, Puma, Synthon and Sanofi. E. Elez: Honoraria (self): Hoffman La-Roche, Bristol Myers Squibb, Servier, Amgen, Merck Serono, Array, Sanofi; Advisory / Consultancy: Hoffman La-Roche, Bristol Myers Squibb, Servier, Amgen, Merck Serono, Array, Sanofi; Research grant / Funding (self): Hoffman La-Roche, Bristol Myers Squibb, Servier, Amgen, Merck Serono, Array, Sanofi; Honoraria (institution): Array, MSD, Abbvie, Amgen, GSK, AstraZeneca, Bristol Myers Squibb, Novartis, Boehringer, Ingelheim, Hoffman La-Roche.. E. Felip: Speaker Bureau / Expert testimony: AbbVie, AstraZeneca, Blueprint medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Guardant Health, Janssen, Medscape, Merck KGaA, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Takeda, Touchtime.; Advisory / Consultancy: AbbVie, AstraZeneca, Blueprint medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Eli Lilly, Guardant Health, Janssen, Medscape, Merck KGaA, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Takeda, Touchtime.; Research grant / Funding (institution): Fundaci on Merck Salud, Grant for Oncology Innovation EMD Serono. A. Oaknin: Advisory / Consultancy: Roche, AstraZeneca, PharmaMar, Clovis Oncology, Tesaro, Inmunogen and Genmab; Travel / Accommodation / Expenses: Roche, AstraZeneca, and PharmaMar. E. Mu~ noz-Couselo: Advisory / Consultancy: Amgen, Bristol-Myers Squibb, Merck, Sharp & Dohme, Novartis, Pierre Fabre, and Roche; Honoraria (self): Amgen, Bristol-Myers Squibb, Merck, Sharp & Dohme, Novartis, Pierre Fabre, Sanofi and Roche ; Leadership role, Clinical trial participation (principal investigator): Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Merck, Sharp & Dohme, Novartis, Pierre Fabre, and Roche. T. Macarulla Mercade: Advisory / Consultancy: Shire Pharmaceuticals, Roche, Tesaro, Batxer, Sanofi, Celgene, QED Therapeutics, Genzyme Europe, Baxalta, Bayer, Incyte, Genzyme ; Travel / Accommodation / Expenses: from Merck, H3 Biomedicine, Bayer, Sanofi. M. Alsina Maqueda: Advisory / Consultancy: Servier, Lilly, BMS and MS. Honoraria for speaking issues from Servier, BMS, MSD, Lilly, Roche and Amge; Travel / Accommodation / Expenses: Servier, Roche, Amgen and Lilly. J. Carles: Advisory / Consultancy: Bayer / Johnson & Johnson / Bristol-Myers Squibb / Astellas Pharma / Pfizer / Sanofi / MSD Oncology / Roche/ AstraZe´neca; Speaker Bureau / Expert testimony: Bayer / Johnson & Johnson / Asofarma / Astellas Pharma; Research grant / Funding (institution): AB Science, Aragon Pharmaceuticals, Arog Pharmaceuticals, INC, Astellas Pharma., AstraZeneca AB, Aveo Pharmaceuticals INC, Bayer AG, Blueprint Medicines Corporation, BN Immunotherapeutics INC, Boehringer Ingelheim Espa~ na, S.A., Bristol-Myers Squibb Inter. R. Dienstmann: Advisory / Consultancy: Roche; Research grant / Funding (self): Merck. J. Tabernero: Advisory / Consultancy: Array Biopharma, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Chugai, Genentech, Inc., Genmab A/S, Halozyme, Imugene Limited, Inflection Biosciences Limited, Ipsen, Kura Oncology, Lilly, MSD, Menarini, Merck Serono, Merrimack, Merus, Molecular Part. E. Garralda: Advisory / Consultancy: F.Hoffmann-La Roche, Ellipses Pharma, Neomed Therapeutics1 Inc, Boehringer Ingelheim, Janssen Global Services, ; Speaker Bureau / Expert testimony: BristolMayers Squibb ; Travel / Accommodation / Expenses: Merck Sharp & Dohme, Glycotope, Menarini; Research grant / Funding (self), Scitron Project - VHIO Technology : Novartis; Research grant / Funding (institution), Clinical Trial Principal Investigator: Principia Biopharma Inc, Lilly, S.A, Novartis, Genentech, Loxo Oncologi Inc, F.Hoffmann-La Roche Ltd, Symphogen A/S, Merck, Sharp & Dohme de Espa~ na, S.A, Incyte Biosciences International, Pharma Mar, S.A.U, Kura Oncology Inc, Macrogenics Inc, Glycotope G; Leadership role: ESMO Women for Oncology - W4O. All other authors have declared no conflicts of interest.
1887P
Development of a comprehensive next-generation targeted sequencing assay for detection of gene-fusions in solid tumors
V.K. Mittal1, S.P. Myrand1, D. Cyanam1, P.D. Williams1, G.G. Bee2, A. Marcovitz3, R. Gottimukkala3, F. Hyland4, C. Allen5, E. Wong-Ho3, S. Sadis1, C. Van Loy2, J. Kilzer2, N. Khazanov1 1 Clinical Sequencing Division, Thermo Fisher Scientific, Ann Arbor, MI, USA, 2Clinical Sequencing Division, Thermo Fisher Scientific, Carlsbad, CA, USA, 3Clinical Sequencing Division, Thermo Fisher Scientific, South San Francisco, CA, USA, 4CSD, Thermo Fisher Scientific, San Francisco, USA, 5Field Applications, Thermo Fisher Scientific, Paisley, UK Background: Gene fusions caused by chromosomal rearrangements play an important role in oncogenesis, the progression of cancer and the selection of targeted therapies. Next-generation sequencing (NGS) using RNA enables sensitive, specific and precise detection of potentially clinically relevant gene fusions, especially when the fusion breakpoint is known. We have developed an NGS solution appropriate for FFPE tissues to detect fusion biomarkers in routine clinical research. Methods: Fusion content was selected based on prioritization of actionability, verified fusion isoforms reported in the literature and collaborations, as well as prevalence of solid tumor fusion driver genes. The assay was designed to use Ion AmpliSeq multiplex
v766 | Translational Research
PCR chemistry using manual or automated library preparation, automated templating on the Ion Chef, and sequencing on the Ion Torrent GeneStudioTM S5 sequencing platform. The analysis was supported by fully automated analysis software that performs sample QC, read-filtering, fusion calling and reporting. Streamlined access to decision support software was enabled by OncomineTM Reporter. Results: Over 1200 targeted isoforms from over 50 known fusion driver genes were incorporated into the assay that included prominent fusion drivers such as ALK, RET, ROS1, NTRK1/2/3 and FGFR1/2/3, and intragenic fusion events in MET, EGFR, BRAF and AR. The assay also reported non-targeted fusion events in relevant driver genes by using a novel statistically significant expression imbalance algorithm comparing 5’and 3’- end gene expression. A preliminary development study was performed using commercially available total RNA for a Tri-Fusion control and SeraseqTM Fusion RNA Mix v3 where all of the expected fusions were detected with 100% sensitivity and specificity. Results were also concordant when characterized FFPE tumor samples with known fusion targets were tested using the assay. Conclusions: A comprehensive NGS assay was developed to support clinical research in oncology for detecting relevant RNA structural alterations from solid tumor FFPEs. An update on assay performance will be presented. Legal entity responsible for the study: Thermo Fisher Scientific. Funding: Has not received any funding. Disclosure: V.K. Mittal: Shareholder / Stockholder / Stock options, Full / Part-time employment: Thermo Fisher Scientific. S.P. Myrand: Shareholder / Stockholder / Stock options, Full / Part-time employment: Thermo Fisher Scientific. D. Cyanam: Shareholder / Stockholder / Stock options, Full / Part-time employment: Thermo Fisher Scientific. P.D. Williams: Shareholder / Stockholder / Stock options, Full / Part-time employment: Thermo Fisher Scientific. G.G. Bee: Shareholder / Stockholder / Stock options, Full / Part-time employment: Thermo Fisher Scientific. A. Marcovitz: Shareholder / Stockholder / Stock options, Full / Part-time employment: Thermo Fisher Scientific. R. Gottimukkala: Shareholder / Stockholder / Stock options, Full / Part-time employment: Thermo Fisher Scientific. F. Hyland: Shareholder / Stockholder / Stock options, Full / Part-time employment: Thermo Fisher Scientific. C. Allen: Shareholder / Stockholder / Stock options, Full / Part-time employment: Thermo Fisher Scientific. E. Wong-Ho: Shareholder / Stockholder / Stock options, Full / Part-time employment: Thermo Fisher Scientific. S. Sadis: Shareholder / Stockholder / Stock options, Full / Part-time employment: Thermo Fisher Scientific. C. Van Loy: Shareholder / Stockholder / Stock options, Full / Part-time employment: Thermo Fisher Scientific. J. Kilzer: Shareholder / Stockholder / Stock options, Full / Part-time employment: Thermo Fisher Scientific. N. Khazanov: Shareholder / Stockholder / Stock options, Full / Part-time employment: Thermo Fisher Scientific.
1888P
Next-generation sequencing for better treatment strategy of cancer of unknown primary (CUP)
K.K. Lee1, M. Kim2, K-M. Kim3, S.T. Kim4, J. Lee4, S.J. Lee5 Hemato-Oncology, Dongsan Medical Center Kemyung University Hospital, Daegu, Republic of Korea, 2Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Republic of Korea, 3Pathology, Samsung Medical Center, Seoul, Republic of Korea, 4Medicine, Samsung Medical Center, Seoul, Republic of Korea, 5Internal Medicine, EWHA Womans University Seoul Hospital, Seoul, Republic of Korea
1
Background: Cancer of unknown primary (CUP) consists of diverse histology types of cancer and have shown poor prognosis. In the era of precision medicine, next-generation sequencing (NGS) may contribute new therapeutic target which could improve treatment outcomes of CUP. Methods: Patients who were diagnosed with CUP and underwent NGS exam between August 2017 and August 2018 at Samsung medical center were included for the study. NGS data were analyzed, and medical records were reviewed retrospectively to evaluate clinical characteristics and response to various treatments. Results: A total of 21 patients with CUP who had NGS data were analyzed. The median age was 58 (range, 35-78 years). Male was dominant (57.1%) and most of the patients were ECOG 1 (90.5%). Among the patients, 14 (66.7%) were poorly differentiated carcinoma, 6 (28.6%) patients were adenocarcinoma, and one patient was squamous cell carcinoma. Most common metastatic site was lymph node (57.1%), followed by bone (38.1%), lung (19.0%), pleura (19.0%). Paclitaxel combined with carboplatin was most frequently used regimen for the first-line treatment (57.1%). Cisplatin-based chemotherapy was used second most (28.6%). One patient showed complete remission during the first-line treatment whereas 7 patients and 5 patients achieved the best response of partial response and stable disease, respectively. Median progression-free survival was 4 months (95% CI: 0.316-7.684), and median overall survival was not reached. Except four patients, 17 (81.0%) patients showed 25 gene alterations on the NGS results. TP53 mutation was observed most commonly (n ¼ 6, 25.6%), followed by ERBB2 alterations (n ¼ 3, mutations [n ¼ 2], amplification [n ¼ 1]), KRAS mutation (n ¼ 2), MET amplification (n ¼ 2), CDKN2A deletion (n ¼ 2), and MYC amplification (n ¼ 2). One patient harbored ERBB2 amplification was treated with trastuzumab combined with paclitaxel, and the patient demonstrated sustained partial response at 9 months, until the data cut-off date. Conclusions: Most of CUP patients had variety actionable gene alterations. Precision medicine based on molecular analysis with NGS will improve the prognosis of the patients with CUP. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
Volume 30 | Supplement 5 | October 2019
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz268.013/5576315 by guest on 26 October 2019
under ultrasound (60%), computed tomography (12%) guidance or non-guided (28%). Samples were formalin-fixed and paraffin embedded (FFPE, 48%), snap frozen (20%) or alternatively stabilized (32%) according to study protocol. Tumor content (TC) was determined in 1514 FFPE samples: 90% of them had tumor cells, 81% showed more than 10% TC and 59% more than 50% TC. No significant difference in TC was found between screening and on-treatment biopsies (p ¼ 0.12). Sample quality was negatively affected by biopsy site (<10% TC rates in non-visceral vs visceral were 26% vs 14%, respectively, p<.0001), method (non-guided vs guided, 37% vs 17%, p<.0001), and operator expertise (<50 vs > 50 biopsies x year, 31% vs 16.5%, p<.0001). In a multivariate logistic model, biopsy site and method were independent determinants of poor sample quality (<10% TC). Within the same biopsy procedure, inter-sample variability was low with 77% of samples showing between 0% to 30% difference in TC. Among 134 intra-trial sequential biopsies with available TC assessment, only 25% pairs were not suitable for performing downstream comparative analyses (<10% TC). Conclusions: Our experience provides important information to improve research biopsy effectiveness in a biomarker program linked to clinical trials. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: P.G. Nuciforo: Honoraria (self): Bayer; Honoraria (self): Novartis; Honoraria (self):
Annals of Oncology