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Metastatic cancer whole-exome sequencing in daily practice
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/mdz268.012/5576305 by guest on 24 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.
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/mdz268.012/5576305 by guest on 24 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.