- Email: [email protected]
translational study for nivolumab treatment in advanced gastric cancer: JACCRO GC-08 (DELIVER trial)
Annals of Oncology 30 (Supplement 6): vi45, 2019 doi:10.1093/annonc/mdz334
MS1 1
Anti-PD-1 therapy as monotherapy and the development of biomarkers for patient selection in gastroesophageal cancers
Manish A. Shah Division of Hematology and Medical Oncology, Weill Cornell Medicine, NewYorkPresbyterian Hospital Gastroesophageal cancers, eg cancers of the stomach and esophagus, are a leading cause of cancer related death worldwide. Recent evidence suggests that these cancers are complex and heterogeneous diseases with emerging subtypes shown to influence response to treatment and survival. Immunotherapy is an advancing field and immune checkpoint inhibitors have become standard treatment options in numerous tumor types and is emerging therapy in gastroesophageal malignancies. Several immune checkpoint inhibitors have been examined in gastric and esophageal cancers, both as single agents and in combination with cytotoxic therapy. Tumors with deficiency in mismatch repair have demonstrated considerable activity with single agent immunotherapy. These tumors, typically characterized by loss or inactivation of DNA repair proteins MLH1, MSH2, MSH6, and PMS2, accumulate hundreds to thousands of mutations in the microsatellite regions of DNA during replication, mutations that would normally be repaired if the mismatch repair system were intact. These tumors are noted to have high lymphocytic infiltrates, and are primed for an anti-tumor immune response by host immunity, with high single agent immunotherapy activity of 50% response rates. However across several studies, particularly without patient selection or by selection based on PD-L1 expression alone, the response rates to anti-PD-1 or anti-PD-L1 therapy in gastric and esophageal cancer is marginal, ranging from 5-15%. The most compelling and transformative aspect of immunotherapy is that the few patients who do respond have durable responses, often greater than 1 year, generally with minimal side effects. Our challenge is to better select patients who will benefit from single agent immunotherapy. We will discuss the emerging data examining immunotherapy in upper gastrointestinal malignancies across first, second, and third line studies and the development of biomarkers to improve patient selection.
MS1 4
A Biomarker Analysis of Nivolumab in Previously Treated Advanced Gastric Cancer (WJOG10417GTR)
Hirokazu Shoji1, Chie Kudo-Saito2, Hiromasa Takaishi3, Naoki Takahashi4, Tadamichi Denda5, Takeshi Kawakami6, Kensei Yamaguchi7, Junji Furuse8, Toshikazu Moriwaki9, Toshimi Takano10, Ryoichi Sawada11, Takahiro Miyamoto1, Hiroshi Imazeki1, Kazunori Aoki2, Kei Muro12, Narikazu Boku1 1 Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, 2 Department of Immune Medicine, National Cancer Center Research Institute, 3 Department of Internal Medicine, Division of Gastroenterology and Hepatology, Keio University School of Medicine, 4Department of Gastroenterology, Saitama Cancer Center, 5Division of Gastroenterology, Chiba Cancer Center, 6Division of Gastrointestinal Oncology, Shizuoka Cancer Center, 7Department of Gastroenterology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, 8Department of Medical Oncology, Kyorin University Faculty of Medicine, 9Division of Gastroenterology, Faculty of Medicine, University of Tsukuba, 10Department of Medical Oncology, Toranomon Hospital, 11Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, 12Department of Clinical Oncology, Aichi Cancer Center Hospital
treatment. In Japan, nivolumab was approved for unresectable advanced gastric cancer in 2017, and its monotherapy is recommended as the standard treatment in the third or later line treatment in the Gastric Cancer Treatment Guidelines 2018. However, the response rate of the nivolumab monotherapy is only about 10%, and no therapeutic efficacy has been seen in about a half of the treated patients. In addition, pembrolizumab (also anti-PD-1 mAb) failed to show superiority to the weekly-paclitaxel in the Keynote-061 trial for PD-L1-positive (CPS > 1%) advanced gastric cancer. Thus, since the treatment efficacy of blocking PD-1 in gastric cancer is limited, it is urgently necessary for the treatment selection to establish more useful biomarkers. Methods: The WJOG10417GTR is a translational research using fresh and unfrozen specimens harvested from gastric cancer patients treated with nivolumab monotherapy. Peripheral blood, endoscopic biopsy samples are collected at 3 time points (before initiating treatment, about 1 month after treatment, and at disease progression), and systems oncoimmunology is being conducted by analyzing gene expression, pathological features of tumor tissues, soluble molecules in plasma, and phenotypes of immune cells by flow cytometry. Then, the relationship between these data and the clinicopathological characteristics including the response to nivolumab will be statistically evaluated. Eleven hospitals are collaborating in this study toward the goal of 100 patient’s enrollment in July 2018. Thirty-three patients have been registered until May 2019.
MS1 5½Encore
An observational/translational study for nivolumab treatment in advanced gastric cancer: JACCRO GC-08 (DELIVER trial)
Yu Sunakawa Department of Clinical Oncology, St. Marianna University School of Medicine Background: Nivolumab (Nivo) demonstrated survival benefit and a manageable safety profile in previously treated patients (pts) with gastric cancer (GC) or gastroesophageal junction (GEJ) cancer in the ATTRACTION-2 trial, providing an objective response rate (ORR) of 11% and a disease control rate (DCR) of 40% (Lancet 2017). There are few real-world data of Nivo and its predictive markers are needed in GC. It has been demonstrated that the efficacy of anti-PD-1-based immunotherapy was associated with composition of gut microbiome in various types of cancers (Science 2017), but little is known about GC. We therefore investigate whether host-related immunefactors will serve as predictors for Nivo in GC. Trial design: This is an observational/translational study to evaluate efficacy and safety of Nivo for advanced GC in real world, and to discover novel immune-related biomarkers for Nivo. It has been enrolling pts with advanced GC treated with Nivo alone in any lines, up to 500 pts from March 2018. Eligible pts must have: adenocarcinoma of the stomach or GEJ; recurrent or metastatic disease; ECOG PS 0-2; willing to undergo 2 collections of stool and blood in the study. ORR, DCR, progression-free survival, overall survival, tumor shrinkage rate, and tumor progression rate are evaluated as the efficacy. Translational approach will be performed to identify host immune-related factors (gut microbiome, genetic polymorphism, gene expression, and metabolome in plasma) as predictors for efficacy and safety of Nivo, using fecal and blood samples. The samples will be collected before and after Nivo treatment. Candidate factors will be explored in first 200 pts and then validated in last 300 pts. An association of gut microbiome with efficacy of Nivo evaluated by first imaging, primary endpoint of the approach, will be investigated using metagenomics analyses. Secondary endpoints include associations between other immune-biomarkers and clinical outcomes of Nivo (UMIN000030850).
Background: Nivolumab (anti-PD-1 mAb) is a promising drug that survival benefit has been proven in a phase III trial for advanced gastric cancer in third- or later line
C The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology. V
All rights reserved. For permissions, please email: [email protected].
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_6/mdz334.002/5582916 by Universidad Catolica de Temuco user on 25 October 2019
MINI SYMPOSIUM 1 : DEVELOPMENT OF COMBINATION THERAPY USING I-O AGENT FOR UPPER GI TRACT CANCER
MS1 1
Anti-PD-1 therapy as monotherapy and the development of biomarkers for patient selection in gastroesophageal cancers
Manish A. Shah Division of Hematology and Medical Oncology, Weill Cornell Medicine, NewYorkPresbyterian Hospital Gastroesophageal cancers, eg cancers of the stomach and esophagus, are a leading cause of cancer related death worldwide. Recent evidence suggests that these cancers are complex and heterogeneous diseases with emerging subtypes shown to influence response to treatment and survival. Immunotherapy is an advancing field and immune checkpoint inhibitors have become standard treatment options in numerous tumor types and is emerging therapy in gastroesophageal malignancies. Several immune checkpoint inhibitors have been examined in gastric and esophageal cancers, both as single agents and in combination with cytotoxic therapy. Tumors with deficiency in mismatch repair have demonstrated considerable activity with single agent immunotherapy. These tumors, typically characterized by loss or inactivation of DNA repair proteins MLH1, MSH2, MSH6, and PMS2, accumulate hundreds to thousands of mutations in the microsatellite regions of DNA during replication, mutations that would normally be repaired if the mismatch repair system were intact. These tumors are noted to have high lymphocytic infiltrates, and are primed for an anti-tumor immune response by host immunity, with high single agent immunotherapy activity of 50% response rates. However across several studies, particularly without patient selection or by selection based on PD-L1 expression alone, the response rates to anti-PD-1 or anti-PD-L1 therapy in gastric and esophageal cancer is marginal, ranging from 5-15%. The most compelling and transformative aspect of immunotherapy is that the few patients who do respond have durable responses, often greater than 1 year, generally with minimal side effects. Our challenge is to better select patients who will benefit from single agent immunotherapy. We will discuss the emerging data examining immunotherapy in upper gastrointestinal malignancies across first, second, and third line studies and the development of biomarkers to improve patient selection.
MS1 4
A Biomarker Analysis of Nivolumab in Previously Treated Advanced Gastric Cancer (WJOG10417GTR)
Hirokazu Shoji1, Chie Kudo-Saito2, Hiromasa Takaishi3, Naoki Takahashi4, Tadamichi Denda5, Takeshi Kawakami6, Kensei Yamaguchi7, Junji Furuse8, Toshikazu Moriwaki9, Toshimi Takano10, Ryoichi Sawada11, Takahiro Miyamoto1, Hiroshi Imazeki1, Kazunori Aoki2, Kei Muro12, Narikazu Boku1 1 Gastrointestinal Medical Oncology Division, National Cancer Center Hospital, 2 Department of Immune Medicine, National Cancer Center Research Institute, 3 Department of Internal Medicine, Division of Gastroenterology and Hepatology, Keio University School of Medicine, 4Department of Gastroenterology, Saitama Cancer Center, 5Division of Gastroenterology, Chiba Cancer Center, 6Division of Gastrointestinal Oncology, Shizuoka Cancer Center, 7Department of Gastroenterology, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, 8Department of Medical Oncology, Kyorin University Faculty of Medicine, 9Division of Gastroenterology, Faculty of Medicine, University of Tsukuba, 10Department of Medical Oncology, Toranomon Hospital, 11Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, 12Department of Clinical Oncology, Aichi Cancer Center Hospital
treatment. In Japan, nivolumab was approved for unresectable advanced gastric cancer in 2017, and its monotherapy is recommended as the standard treatment in the third or later line treatment in the Gastric Cancer Treatment Guidelines 2018. However, the response rate of the nivolumab monotherapy is only about 10%, and no therapeutic efficacy has been seen in about a half of the treated patients. In addition, pembrolizumab (also anti-PD-1 mAb) failed to show superiority to the weekly-paclitaxel in the Keynote-061 trial for PD-L1-positive (CPS > 1%) advanced gastric cancer. Thus, since the treatment efficacy of blocking PD-1 in gastric cancer is limited, it is urgently necessary for the treatment selection to establish more useful biomarkers. Methods: The WJOG10417GTR is a translational research using fresh and unfrozen specimens harvested from gastric cancer patients treated with nivolumab monotherapy. Peripheral blood, endoscopic biopsy samples are collected at 3 time points (before initiating treatment, about 1 month after treatment, and at disease progression), and systems oncoimmunology is being conducted by analyzing gene expression, pathological features of tumor tissues, soluble molecules in plasma, and phenotypes of immune cells by flow cytometry. Then, the relationship between these data and the clinicopathological characteristics including the response to nivolumab will be statistically evaluated. Eleven hospitals are collaborating in this study toward the goal of 100 patient’s enrollment in July 2018. Thirty-three patients have been registered until May 2019.
MS1 5½Encore
An observational/translational study for nivolumab treatment in advanced gastric cancer: JACCRO GC-08 (DELIVER trial)
Yu Sunakawa Department of Clinical Oncology, St. Marianna University School of Medicine Background: Nivolumab (Nivo) demonstrated survival benefit and a manageable safety profile in previously treated patients (pts) with gastric cancer (GC) or gastroesophageal junction (GEJ) cancer in the ATTRACTION-2 trial, providing an objective response rate (ORR) of 11% and a disease control rate (DCR) of 40% (Lancet 2017). There are few real-world data of Nivo and its predictive markers are needed in GC. It has been demonstrated that the efficacy of anti-PD-1-based immunotherapy was associated with composition of gut microbiome in various types of cancers (Science 2017), but little is known about GC. We therefore investigate whether host-related immunefactors will serve as predictors for Nivo in GC. Trial design: This is an observational/translational study to evaluate efficacy and safety of Nivo for advanced GC in real world, and to discover novel immune-related biomarkers for Nivo. It has been enrolling pts with advanced GC treated with Nivo alone in any lines, up to 500 pts from March 2018. Eligible pts must have: adenocarcinoma of the stomach or GEJ; recurrent or metastatic disease; ECOG PS 0-2; willing to undergo 2 collections of stool and blood in the study. ORR, DCR, progression-free survival, overall survival, tumor shrinkage rate, and tumor progression rate are evaluated as the efficacy. Translational approach will be performed to identify host immune-related factors (gut microbiome, genetic polymorphism, gene expression, and metabolome in plasma) as predictors for efficacy and safety of Nivo, using fecal and blood samples. The samples will be collected before and after Nivo treatment. Candidate factors will be explored in first 200 pts and then validated in last 300 pts. An association of gut microbiome with efficacy of Nivo evaluated by first imaging, primary endpoint of the approach, will be investigated using metagenomics analyses. Secondary endpoints include associations between other immune-biomarkers and clinical outcomes of Nivo (UMIN000030850).
Background: Nivolumab (anti-PD-1 mAb) is a promising drug that survival benefit has been proven in a phase III trial for advanced gastric cancer in third- or later line
C The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology. V
All rights reserved. For permissions, please email: [email protected].
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_6/mdz334.002/5582916 by Universidad Catolica de Temuco user on 25 October 2019
MINI SYMPOSIUM 1 : DEVELOPMENT OF COMBINATION THERAPY USING I-O AGENT FOR UPPER GI TRACT CANCER