|
1
|
Gou M, Zhang H, Qian N, Zhang Y, Sun Z, Li G, Wang Z, Dai G. Deep learning radiomics analysis for prediction of survival in patients with unresectable gastric cancer receiving immunotherapy. Eur J Radiol Open 2025; 14:100626. [PMID: 39807092 PMCID: PMC11728962 DOI: 10.1016/j.ejro.2024.100626] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 12/03/2024] [Accepted: 12/14/2024] [Indexed: 01/16/2025] Open
Abstract
Objective Immunotherapy has become an option for the first-line therapy of advanced gastric cancer (GC), with improved survival. Our study aimed to investigate unresectable GC from an imaging perspective combined with clinicopathological variables to identify patients who were most likely to benefit from immunotherapy. Method Patients with unresectable GC who were consecutively treated with immunotherapy at two different medical centers of Chinese PLA General Hospital were included and divided into the training and validation cohorts, respectively. A deep learning neural network, using a multimodal ensemble approach based on CT imaging data before immunotherapy, was trained in the training cohort to predict survival, and an internal validation cohort was constructed to select the optimal ensemble model. Data from another cohort were used for external validation. The area under the receiver operating characteristic curve was analyzed to evaluate performance in predicting survival. Detailed clinicopathological data and peripheral blood prior to immunotherapy were collected for each patient. Univariate and multivariable logistic regression analysis of imaging models and clinicopathological variables was also applied to identify the independent predictors of survival. A nomogram based on multivariable logistic regression was constructed. Result A total of 79 GC patients in the training cohort and 97 patients in the external validation cohort were enrolled in this study. A multi-model ensemble approach was applied to train a model to predict the 1-year survival of GC patients. Compared to individual models, the ensemble model showed improvement in performance metrics in both the internal and external validation cohorts. There was a significant difference in overall survival (OS) among patients with different imaging models based on the optimum cutoff score of 0.5 (HR = 0.20, 95 % CI: 0.10-0.37, P < 0.001). Multivariate Cox regression analysis revealed that the imaging models, PD-L1 expression, and lung immune prognostic index were independent prognostic factors for OS. We combined these variables and built a nomogram. The calibration curves showed that the C-index of the nomogram was 0.85 and 0.78 in the training and validation cohorts. Conclusion The deep learning model in combination with several clinical factors showed predictive value for survival in patients with unresectable GC receiving immunotherapy.
Collapse
Affiliation(s)
- Miaomiao Gou
- Department of Medical Oncology, The Fifth Medical Center, Chinese People’s Liberation Army General Hospital, Beijing, PR China
| | - Hongtao Zhang
- Department of Medical Oncology, The Fifth Medical Center, Chinese People’s Liberation Army General Hospital, Beijing, PR China
| | - Niansong Qian
- Department of Thoracic Oncology, The Eighth Medical Center, Chinese People’s Liberation Army General Hospital, Beijing, PR China
| | - Yong Zhang
- Department of Medical Oncology, The Second Medical Center, Chinese People’s Liberation Army General Hospital, Beijing, PR China
| | - Zeyu Sun
- R&D Center, Keya Medical Technology Co., Ltd, Beijing, PR China
| | - Guang Li
- R&D Center, Keya Medical Technology Co., Ltd, Beijing, PR China
| | - Zhikuan Wang
- Department of Medical Oncology, The Fifth Medical Center, Chinese People’s Liberation Army General Hospital, Beijing, PR China
| | - Guanghai Dai
- Department of Medical Oncology, The Fifth Medical Center, Chinese People’s Liberation Army General Hospital, Beijing, PR China
| |
Collapse
|
|
2
|
Gordon A, Cunningham D, Rajan Z, Fong C, Peckitt C, Satchwell L, Cromarty S, Kidd S, Piadel K, Leamon B, Zhitkov O, Davidson M, Thompson J, Maisey N, Darby S, Waddell T, Morgan C, Bradshaw A, Petty R, Fribbens C, Rao S, Starling N, Chau I. Maintenance Capecitabine Plus Ramucirumab After First-Line Chemotherapy in Patients With Advanced Esophagogastric Adenocarcinoma: Results From the Randomized PLATFORM Study. JCO ONCOLOGY ADVANCES 2025; 2:e2400073. [PMID: 40330143 PMCID: PMC12053389 DOI: 10.1200/oa-24-00073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Revised: 02/10/2025] [Accepted: 03/27/2025] [Indexed: 05/08/2025]
Abstract
PURPOSE PLATFORM is an adaptive phase II study assessing maintenance therapies in advanced esophagogastric adenocarcinoma (OGA). We evaluated the role of capecitabine plus a vascular endothelial growth factor receptor 2 inhibitor ramucirumab (cape-ram) in these patients. METHODS Human epidermal growth factor receptor 2 (HER2)-negative patients with advanced OGA with stable or responding disease after 18 weeks of induction platinum-based chemotherapy were randomly assigned 1:1 to surveillance or cape-ram. The primary end point was progression-free survival (PFS), and key secondary end points were overall survival (OS) and safety. Recruitment to the cape-ram arm closed prematurely because of industry support withdrawal. A one-sided log-rank test with a 2.5% significance level was considered significant. RESULTS Between April 2019 and November 2022, 25 surveillance and 22 cape-ram patients were contemporaneously randomly assigned. Median follow-up was 24.4 months. Compared with surveillance, cape-ram significantly prolonged PFS (hazard ratio [HR], 0.33 [95% CI, 0.17 to 0.63], P < .001; median PFS: 2.5 months with surveillance versus 5.5 months with cape-ram; 6-month PFS rate: 4% [95% CI, 0.3% to 17.0%] v 42.9% [95% CI, 21.9% to 62.3%], respectively) and OS (HR, 0.51 [95% CI, 0.26 to 1.00], P = .023; median OS: 7.1 months with surveillance v 14.4 months with cape-ram; median OS from start of induction chemotherapy was 12.1 months v 19.5 months, respectively). Of 10 cape-ram patients with measurable disease, 1 had an incremental partial response. Grade ≥3 adverse events (AEs) were seen in 32% surveillance and 57% cape-ram patients. Six cape-ram patients had grade 3 treatment-related AEs, and no new safety signals were identified. CONCLUSION Maintenance cape-ram after induction chemotherapy for patients with HER2-negative OGA significantly improved survival compared with surveillance. To our knowledge, this is the first randomized maintenance study demonstrating survival benefit and provides support for maintenance treatment.
Collapse
Affiliation(s)
- Anderley Gordon
- Gastrointestinal Unit, Department of Medicine, Royal Marsden Hospital, London and Surrey, United Kingdom
| | - David Cunningham
- Gastrointestinal Unit, Department of Medicine, Royal Marsden Hospital, London and Surrey, United Kingdom
| | - Zayn Rajan
- Research Data & Statistics Unit, Royal Marsden Clinical Trials Unit, Royal Marsden Hospital, London and Surrey, United Kingdom
| | - Caroline Fong
- Gastrointestinal Unit, Department of Medicine, Royal Marsden Hospital, London and Surrey, United Kingdom
| | - Clare Peckitt
- Research Data & Statistics Unit, Royal Marsden Clinical Trials Unit, Royal Marsden Hospital, London and Surrey, United Kingdom
| | - Laura Satchwell
- Research Data & Statistics Unit, Royal Marsden Clinical Trials Unit, Royal Marsden Hospital, London and Surrey, United Kingdom
| | - Susan Cromarty
- Gastrointestinal Unit, Department of Medicine, Royal Marsden Hospital, London and Surrey, United Kingdom
| | - Shannon Kidd
- Gastrointestinal Unit, Department of Medicine, Royal Marsden Hospital, London and Surrey, United Kingdom
| | - Katarzyna Piadel
- Gastrointestinal Unit, Department of Medicine, Royal Marsden Hospital, London and Surrey, United Kingdom
| | - Becky Leamon
- Gastrointestinal Unit, Department of Medicine, Royal Marsden Hospital, London and Surrey, United Kingdom
| | - Oleg Zhitkov
- Gastrointestinal Unit, Department of Medicine, Royal Marsden Hospital, London and Surrey, United Kingdom
| | - Michael Davidson
- Gastrointestinal Unit, Department of Medicine, Royal Marsden Hospital, London and Surrey, United Kingdom
| | - Joyce Thompson
- Oncology Department, Heartlands Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom
| | | | - Suzanne Darby
- Weston Park Cancer Centre, Sheffield, United Kingdom
| | - Tom Waddell
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom
| | - Carys Morgan
- Department of Clinical Oncology, Velindre Cancer Centre, Cardiff, United Kingdom
| | | | - Russell Petty
- Division of Molecular and Clinical Medicine, School of Medicine, University of Dundee, Dundee, United Kingdom
| | - Charlotte Fribbens
- Gastrointestinal Unit, Department of Medicine, Royal Marsden Hospital, London and Surrey, United Kingdom
| | - Sheela Rao
- Gastrointestinal Unit, Department of Medicine, Royal Marsden Hospital, London and Surrey, United Kingdom
| | - Naureen Starling
- Gastrointestinal Unit, Department of Medicine, Royal Marsden Hospital, London and Surrey, United Kingdom
| | - Ian Chau
- Gastrointestinal Unit, Department of Medicine, Royal Marsden Hospital, London and Surrey, United Kingdom
| |
Collapse
|
|
3
|
Qin S, Bai Y, Li J, Pan H, Luo S, Qu Y, Ye F, Yang L, Liu T, Li W, Chen X, Yang J, Ying J, Lin X, Zhao L, Liang X, Mao Y, Guo R, Zuo Y, Bordia S, Li S. First-Line Pembrolizumab Plus Chemotherapy for HER2-Negative Advanced Gastric Cancer: China Subgroup Analysis of the Randomized Phase 3 KEYNOTE-859 Study. Adv Ther 2025; 42:1892-1906. [PMID: 40025394 PMCID: PMC11929688 DOI: 10.1007/s12325-024-03069-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Accepted: 11/08/2024] [Indexed: 03/04/2025]
Abstract
INTRODUCTION Results of the global, randomized, phase 3 KEYNOTE-859 study (N = 1579) showed that first-line pembrolizumab plus chemotherapy produced a statistically significant and clinically meaningful improvement in overall survival (OS) with manageable toxicity versus placebo plus chemotherapy in patients with locally advanced or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric or gastroesophageal junction cancer. This subgroup analysis was conducted to investigate outcomes in patients enrolled in mainland China. METHODS Adults with previously untreated advanced or metastatic HER2-negative gastric cancer or gastroesophageal junction adenocarcinoma were randomly assigned (1:1) to receive pembrolizumab or placebo with fluoropyrimidine- and platinum-containing chemotherapy. The primary outcome was OS. Secondary outcomes included progression-free survival (PFS), objective response rate (ORR), and duration of response (DOR), all assessed per RECIST v1.1 by blinded independent central review, and safety. RESULTS Overall, 236 patients were enrolled in mainland China (126 pembrolizumab plus chemotherapy; 110 placebo plus chemotherapy). Median time from randomization to database cutoff (October 3, 2022) was 24.7 months (range 15.3-38.9). Median OS was 15.9 months (95% confidence interval [CI] 13.2-19.2) for pembrolizumab plus chemotherapy versus 12.2 months (95% CI 10.6-14.1) for placebo plus chemotherapy (hazard ratio [HR], 0.68; 95% CI 0.50-0.91). Median PFS was 8.1 months (95% CI 6.9-9.6) for pembrolizumab plus chemotherapy versus 5.7 months (95% CI 4.5-6.5) for placebo plus chemotherapy (HR, 0.65; 95% CI 0.48-0.88). ORR was 69.0% for pembrolizumab plus chemotherapy versus 45.5% for placebo plus chemotherapy; median DOR was 8.2 months (range 1.2+ to 34.6+) versus 5.5 months (range 1.3+ to 31.2+), respectively. Grade 3-5 treatment-related adverse events occurred in 82 patients (65.6%) treated with pembrolizumab plus chemotherapy and 54 patients (49.1%) treated with placebo plus chemotherapy. CONCLUSION Consistent with efficacy in the overall population from KEYNOTE-859, first-line pembrolizumab plus chemotherapy showed improved efficacy, versus placebo plus chemotherapy, and manageable safety in patients enrolled in mainland China. TRIAL REGISTRATION Clinicaltrials.gov: NCT03675737.
Collapse
Affiliation(s)
- Shukui Qin
- GI Cancer Center, Nanjing Tianyinshan Hospital of China Pharmaceutical University, No 3789, Jieyin Road, Jiangning District, Nanjing, 210000, Jiangsu, China.
- Cancer Center of People's Liberation Army, Nanjing, China.
| | - Yuxian Bai
- Harbin Medical University Cancer Hospital, Harbin, China
| | - Jin Li
- Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Hongming Pan
- Zhejiang University School of Medicine, Sir Run Shaw Hospital, Hangzhou, China
| | - Suxia Luo
- The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, China
| | - Yanli Qu
- Cancer Hospital Affiliated to Xinjiang Medical University, Xinjiang, China
| | - Feng Ye
- The First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Lin Yang
- National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Tianshu Liu
- Zhongshan Hospital Affiliated to Fudan University, Shanghai, China
| | - Wei Li
- The First Hospital of Jilin University, Changchun, China
| | - Xi Chen
- The 900th Hospital of the Joint Logistics Support Force of the Chinese People's Liberation Army, Fuzhou, China
| | - Jianwei Yang
- Fujian Provincial Cancer Hospital, Fuzhou, China
| | - Jieer Ying
- Zhejiang Cancer Hospital, Hangzhou, China
| | - Xiaoyan Lin
- Fujian Medical University Union Hospital, Fuzhou, China
| | - Lin Zhao
- Peking Union Medical College Hospital, Beijing, China
| | | | | | | | - Yi Zuo
- MSD China, Beijing, China
| | | | - Shouguo Li
- Zhongshan Hospital Affiliated to Xiamen University, Xiamen, China
| |
Collapse
|
|
4
|
Wu JW, Zhou CF, Han ZX, Zhang H, Yan J, Chen J, Wang CB, Qin ZQ, Mao Y, Tang XY, Zhu LJ, Wei XW, Cui DH, Yang XL, Shi M, Zhao LQ, Jiang JL, Zhu WY, Wang HM, Wang C, Zhu LJ, Zhang J. Anlotinib plus chemotherapy as a first-line treatment for gastrointestinal cancer patients with unresectable liver metastases: a multicohort, multicenter, exploratory trial. Signal Transduct Target Ther 2024; 9:344. [PMID: 39648217 PMCID: PMC11625826 DOI: 10.1038/s41392-024-02051-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 10/26/2024] [Accepted: 11/04/2024] [Indexed: 12/10/2024] Open
Abstract
This multicohort phase II trial (ALTER-G-001; NCT05262335) aimed to assess the efficacy of first-line anlotinib plus chemotherapy for gastrointestinal (GI) cancer patients with unresectable liver metastases. Eligible patients with colorectal cancer (Cohort A) or noncolorectal and nonesophageal GI cancer (Cohort C) received six cycles of anlotinib plus standard chemotherapeutic regimens followed by anlotinib plus metronomic capecitabine as a maintenance therapy. Liver metastasectomy can be performed when liver metastases are converted to resectable lesions. The primary outcome was the investigator-confirmed objective response rate (ORR) in the intention-to-treat population. Among the 47 patients in Cohort A, the ORR was 40.4% (95% CI 26.4-55.7), including 1 with a complete response (CR) and 18 who achieved a partial response (PR). The median progression-free survival (PFS) was 8.7 months (95% CI 7.3-NE), and the median overall survival (OS) was not reached. In Cohort C, 14 of 44 patients achieved a PR, with an ORR of 31.8% (95% CI 18.6-47.6). The PFS and OS were 5.8 months (95% CI 4.8-6.5) and 11.4 months (95% CI 5.8-19.3), respectively. The liver metastasectomy rate in patients with liver-limited disease was 22.7% (5/22) in Cohort A and 6.7% (2/30) in Cohort C. For pancreatic cancer patients, the ORR of the efficacy-evaluable population was 36.0% (9/25), and those with liver-limited metastasis had better survival. Moreover, no new safety concerns emerged. In conclusion, an anlotinib-based first-line regimen demonstrated promising antitumor activity among GI cancer patients with unresectable liver metastases and led to liver metastasectomy in selected patients.
Collapse
Affiliation(s)
- Jun-Wei Wu
- Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chen-Fei Zhou
- Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zheng-Xiang Han
- Department of Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Huan Zhang
- Department of Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jun Yan
- Department of Oncology, Jiading District Central Hospital Affiliated Shanghai University of Medicine & Health Sciences, Shanghai, China
| | - Jun Chen
- Department of Chemoradiotherapy, The Affiliated People's Hospital of Ningbo University, Ningbo, China
| | - Chun-Bin Wang
- Department of Oncology, The Third People's Hospital of Yancheng, Yancheng, China
| | - Zhi-Quan Qin
- Department of Medical Oncology, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou, China
| | - Yong Mao
- Department of Oncology, Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Xin-Yu Tang
- Department of Oncology, Wuxi Branch of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Wuxi, China
| | - Liang-Jun Zhu
- Department of Medical Oncology, Jiangsu Cancer Hospital, Nanjing, China
| | - Xiao-Wei Wei
- Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Dong-Hai Cui
- Department of Internal Medicine, Anyang Tumor Hospital, Anyang, China
| | - Xiu-Li Yang
- Department of Oncology, First Affiliated Hospital of Nanyang Medical College, Nanyang, China
| | - Min Shi
- Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Li-Qin Zhao
- Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jin-Ling Jiang
- Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wei-You Zhu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Hong-Mei Wang
- Department of Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Chun Wang
- Department of Oncology, Jiading District Central Hospital Affiliated Shanghai University of Medicine & Health Sciences, Shanghai, China
| | - Ling-Jun Zhu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
| | - Jun Zhang
- Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| |
Collapse
|
|
5
|
Wang P, Chen P, Yang W, Yang W, Liu W, Yue S, Luo Q. Prognostic and predictive factors in advanced upper gastrointestinal cancer treated with immune checkpoint inhibitors: a systematic review and meta-analysis of the current evidence. BMC Cancer 2024; 24:1249. [PMID: 39385078 PMCID: PMC11465923 DOI: 10.1186/s12885-024-12998-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Accepted: 09/26/2024] [Indexed: 10/11/2024] Open
Abstract
BACKGROUND Immune checkpoint inhibitors (ICIs) have shown encouraging treatment efficacy for upper gastrointestinal cancers (UGICs). However, durable clinical responses only existed in a minority of patients. We evaluated evidence predicting survival benefits to identify the optimal population followed by ICI-based therapy. METHODS A comprehensive search was performed using PubMed, Embase, Cochrane Library, and Web of Science to identify clinical trials for UGICs with ICI-based therapy. The outcomes were objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). The quality of evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation System (GRADE). RESULTS Thirty-six studies comprising 12,440 patients were included for quantitative synthesis. Patients with PD-L1-positive (OR = 2.08, p < 0.00001), EBV+ (OR = 8.47, p = 0.003) tumors were more likely to respond to ICI treatment. Moreover, OS was significantly improved with the statistical subgroup difference concerning sex (p = 0.02) and region (p = 0.02). An exploratory subgroup analysis showed significantly improved OS with ICI plus chemotherapy in patients with CPS ≥ 10 (HR = 0.66, p = 0.001) and CPS ≥ 1 (HR = 0.75, p < 0.00001). CONCLUSION UGIC patients with PD-L1-positive, EBV + status are associated with a better therapeutic response to ICI-based therapy. The male patients and Asian patients could derive more survival benefits following ICI treatment than female and non-Asian ones. A combination of prognostic and predictive factors was suggested to help guide immunotherapy decision-making in UGIC patients.
Collapse
Affiliation(s)
- Puxiu Wang
- Department of Pharmacy, The First Hospital of China Medical University, Shenyang, Liaoning, PR China
- School of Pharmacy, China Medical University, Shenyang, Liaoning, PR China
| | - Ping Chen
- Department of Pharmacy, The First Hospital of China Medical University, Shenyang, Liaoning, PR China
- School of Pharmacy, China Medical University, Shenyang, Liaoning, PR China
| | - Weiting Yang
- Department of Pharmacy, The First Hospital of China Medical University, Shenyang, Liaoning, PR China
- School of Pharmacy, China Medical University, Shenyang, Liaoning, PR China
| | - Wenhan Yang
- Department of Pharmacy, The First Hospital of China Medical University, Shenyang, Liaoning, PR China
- School of Pharmacy, China Medical University, Shenyang, Liaoning, PR China
| | - Wenqi Liu
- School of Life Sciences, Shenyang Pharmaceutical University, Shenyang, Liaoning, PR China
| | - Song Yue
- Department of Pharmacy, The First Hospital of China Medical University, Shenyang, Liaoning, PR China.
- School of Pharmacy, China Medical University, Shenyang, Liaoning, PR China.
| | - Qiuhua Luo
- Department of Pharmacy, The First Hospital of China Medical University, Shenyang, Liaoning, PR China.
- School of Pharmacy, China Medical University, Shenyang, Liaoning, PR China.
| |
Collapse
|
|
6
|
Gao X, Ji K, Jia Y, Shan F, Chen Y, Xu N, Jia Z, Liu T, Yang N, Zhong H, Li C, Guo Z, Fan Q, Lin X, Zhang Y, Ren H, Yang H, Yao Z, Liu W, Wang ZM, Li B, Xia M, Shen L, Li Z, Ji J. Cadonilimab with chemotherapy in HER2-negative gastric or gastroesophageal junction adenocarcinoma: the phase 1b/2 COMPASSION-04 trial. Nat Med 2024; 30:1943-1951. [PMID: 38778212 DOI: 10.1038/s41591-024-03007-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Accepted: 04/17/2024] [Indexed: 05/25/2024]
Abstract
Treatment with anti-programmed cell death protein 1 (PD-1) therapy and chemotherapy prolongs the survival of patients with unresectable advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma. The benefit from anti-PD-1 therapy is enriched in patients with programmed cell death 1 ligand 1 (PD-L1) combined positive score (CPS)-positive or CPS-high tumors compared with patients with PD-L1 CPS-negative or CPS-low tumors. In this phase 1b/2 study, we evaluated the efficacy and safety of cadonilimab, a bispecific antibody targeting PD-1 and cytotoxic T-lymphocyte antigen-4, plus chemotherapy as first-line treatment in patients with human epidermal growth factor receptor 2-negative unresectable advanced or metastatic gastric or GEJ adenocarcinoma. The primary endpoint was the recommended phase 2 dose (RP2D) for phase 1b and the objective response rate for phase 2. Secondary endpoints included disease control rate, duration of response, time to response, progression-free survival, overall survival (OS) and safety. The primary endpoint was met. No dose-limiting toxicities were observed during dose escalation in phase 1b; the recommended phase 2 dose was determined as 6 mg kg-1 every 2 weeks. The objective response rate was 52.1% (95% confidence interval (CI) = 41.6-62.5), consisting of complete and partial responses in 4.3% and 47.9% of patients, respectively. The median duration of response, progression-free survival and OS were 13.73 months (95% CI = 7.79-19.12), 8.18 months (95% CI = 6.67-10.48) and 17.48 months (95% CI = 12.35-26.55), respectively. The median OS in patients with a PD-L1 CPS ≥ 5 was 20.32 months (95% CI = 4.67-not estimable); in patients with a PD-L1 CPS < 1, the median OS reached 17.64 months (95% CI = 11.63-31.70). The most common treatment-related grade 3 or higher adverse events were decreased neutrophil count (19.1%), decreased platelet count (16.0%), anemia (12.8%) and decreased leukocyte count (8.5%). No new safety signal was identified. The current regimen showed promising clinical activity and manageable safety in patients with gastric or GEJ adenocarcinoma regardless of PD-L1 expression. Chinadrugtrials.org.cn registration: CTR20182027.
Collapse
MESH Headings
- Humans
- Stomach Neoplasms/drug therapy
- Stomach Neoplasms/pathology
- Middle Aged
- Male
- Female
- Esophagogastric Junction/pathology
- Adenocarcinoma/drug therapy
- Adenocarcinoma/pathology
- Aged
- Receptor, ErbB-2/metabolism
- Adult
- Esophageal Neoplasms/drug therapy
- Esophageal Neoplasms/pathology
- Antineoplastic Combined Chemotherapy Protocols/therapeutic use
- Antineoplastic Combined Chemotherapy Protocols/adverse effects
- Antibodies, Monoclonal, Humanized/adverse effects
- Antibodies, Monoclonal, Humanized/therapeutic use
- Antibodies, Monoclonal, Humanized/administration & dosage
- Antibodies, Bispecific/therapeutic use
- Antibodies, Bispecific/adverse effects
- Antibodies, Bispecific/administration & dosage
- B7-H1 Antigen/antagonists & inhibitors
Collapse
Affiliation(s)
- Xiangyu Gao
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, Beijing, China
| | - Ke Ji
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, Beijing, China
| | - Yongning Jia
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, Beijing, China
| | - Fei Shan
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, Beijing, China
| | - Ye Chen
- The First Affiliated Hospital, Henan University of Science and Technology, Luoyang, China
| | - Nong Xu
- The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Ziyu Jia
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, Beijing, China
| | | | - Nong Yang
- Hunan Cancer Hospital, Changsha, China
| | | | | | | | - Qingxia Fan
- The First Affiliated Hospital, Zhengzhou University, Zhengzhou, China
| | - Xiaoyan Lin
- Fujian Medical University Union Hospital, Fuzhou, China
| | - Yan Zhang
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, Beijing, China
| | - Hui Ren
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, Beijing, China
| | - Hongxia Yang
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, Beijing, China
| | | | - Wei Liu
- Akeso Biopharma, Inc, Zhongshan, China
| | | | | | | | - Lin Shen
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, Beijing, China.
| | - Ziyu Li
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, Beijing, China.
| | - Jiafu Ji
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, Beijing, China.
| |
Collapse
|
|
7
|
Sun YT, Lu SX, Lai MY, Yang X, Guan WL, Yang LQ, Li YH, Wang FH, Yang DJ, Qiu MZ. Clinical outcomes and biomarker exploration of first-line PD-1 inhibitors plus chemotherapy in patients with low PD-L1-expressing of gastric or gastroesophageal junction adenocarcinoma. Cancer Immunol Immunother 2024; 73:144. [PMID: 38832979 PMCID: PMC11150231 DOI: 10.1007/s00262-024-03721-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Accepted: 05/02/2024] [Indexed: 06/06/2024]
Abstract
BACKGROUND The beneficial effects of first-line programmed death-1 (PD-1) inhibitors plus chemotherapy in patients with low programmed death-ligand 1 (PD-L1)-expressing advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma are controversial. METHODS We conducted a retrospective analysis of patients with G/GEJ adenocarcinoma who had undergone first-line treatment with PD-1 inhibitors plus chemotherapy between October 2017 and May 2022. The primary outcomes were objective response rate (ORR) and progression-free survival (PFS). SPSS software V27.0 was used for data analysis. RESULTS Of 345 enrolled patients, 290 had measurable lesions. The overall ORR was 59.3%. PD-L1 status was available in 171 patients, and 67.8% of them were considered as low PD-L1 expression level (combined positive score (CPS) < 5). Patients with PD-L1 CPS < 5 showed a lower response rate (51.1% vs 70.8%, P = 0.024) and a worse PFS (P = 0.009) compared to those with PD-L1 CPS ≥ 5. In the PD-L1 low-expression cohort, patients with non-diffuse type, GEJ cancer, synchronous metastasis, distant lymph node metastasis, liver metastasis, non-peritoneal metastasis, and HER2 positive were significantly associated with higher response rates to PD-1 inhibitors plus chemotherapy (P < 0.05). The presence of peritoneal metastasis (P = 0.028) and diffuse type (P = 0.046) were identified as independent predictors of poor PFS in multivariate analysis of the PD-L1 CPS < 5 subgroup. When evaluated for correlation with overall survival (OS) in the PD-L1 low-expression subgroup, peritoneal metastasis was found to be the only independent prognostic factor of an increased risk of death (hazard ratio: 2.31, 95% CI 1.09-4.90; P = 0.029). CONCLUSIONS PD-L1 CPS ≥ 5 is significantly associated with improved response and extended PFS in G/GEJ cancer patients treated with a combination of PD-1 inhibitors and chemotherapy. Specific subgroups within the low PD-L1-expressing population, such as those with non-diffuse-type tumors and without peritoneal metastases, may also benefit from immunotherapy combined with chemotherapy.
Collapse
Affiliation(s)
- Yu-Ting Sun
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, 510060, People's Republic of China
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People's Republic of China
| | - Shi-Xun Lu
- Department of Pathology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, 510060, People's Republic of China
| | - Ming-Yu Lai
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, 510060, People's Republic of China
| | - Xia Yang
- Department of Pathology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, 510060, People's Republic of China
| | - Wen-Long Guan
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, 510060, People's Republic of China
| | - Li-Qiong Yang
- Department of Basic Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, 510060, People's Republic of China
| | - Yu-Hong Li
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, 510060, People's Republic of China
| | - Feng-Hua Wang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, 510060, People's Republic of China
| | - Da-Jun Yang
- Department of Basic Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, 510060, People's Republic of China.
| | - Miao-Zhen Qiu
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University, Guangzhou, 510060, People's Republic of China.
| |
Collapse
|
|
8
|
Takayama T, Tsuji Y. Updated Adjuvant Chemotherapy for Gastric Cancer. J Clin Med 2023; 12:6727. [PMID: 37959193 PMCID: PMC10648766 DOI: 10.3390/jcm12216727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 10/03/2023] [Accepted: 10/18/2023] [Indexed: 11/15/2023] Open
Abstract
Surgical resection is currently the best curative approach for gastric cancer (GC); however, the prognosis of patients with advanced GC remains poor even with curative resection. For this reason, perioperative chemotherapy has been combined with surgery to reduce the risk of postoperative recurrence. Standard perioperative chemotherapy for resectable advanced GC varies from region to region. Postoperative S-1 therapy was standardized via the ACTS-GC study in East Asia, perioperative ECF (Epirubicin + Cisplatin + Fluorouracil) was standardized via the MAGIC study in Europe, and postoperative chemoradiotherapy was standardized via the US intergroup study in North America. Since then, more intensive regimens have been developed. In recent years, perioperative therapy using novel agents, such as molecular-targeted drugs and immune checkpoint inhibitors (ICIs), has also been tested and evaluated in the three major regions (East Asia, Europe, and North America) with promising results. Perioperative chemotherapy has become an integral part of many treatment strategies and requires continued research and evaluation.
Collapse
Affiliation(s)
- Toshizo Takayama
- Department of Medical Oncology, Tonan Hospital, Sapporo 060-0004, Japan
- Department of Medical Oncology, Daido Hospital, Nagoya 457-8511, Japan
| | - Yasushi Tsuji
- Department of Medical Oncology, Tonan Hospital, Sapporo 060-0004, Japan
| |
Collapse
|
|
9
|
Li LL, Pan LS. Prognostic value of neutrophil-to-lymphocyte ratio in gastric cancer patients treated with immune checkpoint inhibitors: A meta-analysis. Kaohsiung J Med Sci 2023; 39:842-852. [PMID: 37166079 DOI: 10.1002/kjm2.12694] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 03/26/2023] [Accepted: 04/17/2023] [Indexed: 05/12/2023] Open
Abstract
The neutrophil-to-lymphocyte ratio (NLR) has been extensively studied in patients with gastric cancer (GC) treated with immune checkpoint inhibitors (ICIs), although the results are controversial. Therefore, we performed the present meta-analysis to systematically assess the correlation between NLR and prognosis and clinicopathological factors in GC patients undergoing treatment with ICIs. Among the electronic databases, PubMed, Web of Science, Embase, and Cochrane Library were thoroughly searched. To estimate the prognostic value of NLR for progression-free survival (PFS) and overall survival (OS), hazard ratios (HRs) were calculated, and their 95% confidence intervals were calculated. This meta-analysis included 10 studies with 830 patients. Based on the pooled data, a high NLR was associated with poor OS in GC patients receiving ICIs (HR = 2.13, 95% confidence interval [CI] = 1.70-2.66, p < 0.001). Elevated NLR was a significant biomarker for worse PFS in GC patients treated with ICIs (HR = 1.74, 95% CI = 1.22-2.48, p = 0.002). There was, however, no significant correlation between NLR and sex, age, and Eastern Cooperative Oncology Group Performance Status (PS) of the ECOG, differentiation, human epidermal growth factor receptor 2 (HER2) status, or PD-L1 status in GC patients treated with ICIs. High NLR before treatment was associated with poor OS and PFS in GC patients treated with ICIs, according to our meta-analysis. NLR is an effective biomarker for evaluating the prognosis of GC patients receiving ICIs and provide more valuable information for treatment decisions in the era of immunotherapy for GC.
Collapse
Affiliation(s)
- Li-Li Li
- Clinical Laboratory, Huzhou Central Hospital, Affiliated Central Hospital of Huzhou University, Huzhou, Zhejiang, China
| | - Li-Sha Pan
- Clinical Laboratory, Huzhou Central Hospital, Affiliated Central Hospital of Huzhou University, Huzhou, Zhejiang, China
| |
Collapse
|
|
10
|
Noori M, Fayyaz F, Zali MR, Bashash D. Predictive value of PD-L1 expression in response to immune checkpoint inhibitors for gastric cancer treatment: a systematic review and meta-analysis. Expert Rev Anticancer Ther 2023; 23:1029-1039. [PMID: 37466449 DOI: 10.1080/14737140.2023.2238896] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2022] [Revised: 06/04/2023] [Accepted: 06/27/2023] [Indexed: 07/20/2023]
Abstract
BACKGROUND Which patients may benefit more from immune checkpoint inhibitors (ICIs) is still an important question. The present study aimed to investigate the role of the PD-L1 molecule in predicting the effectiveness of PD-1/PD-L1 inhibitors in gastric cancer patients. METHOD We searched PubMed, Scopus, Web of Science, and EMBASE databases as of 25 March 202225 March 2022. RESULTS Ten articles were included. When we used the TPS method for PD-L1 expression, none of the patients in tumor proportion score (TPS)≥1% and TPS < 1% groups took advantage of ICI therapy in terms of OS and PFS. However, gastric cancer patients with combined-positive score (CPS)≥1, CPS ≥ 5, and CPS ≥ 10 tumors represented superior OS for ICIs over the control agents, while their counterparts (i.e. patients with CPS < 1, CPS < 5, and CPS < 10 tumors) did not. In the subgroup analysis when patients with CPS ≥ 1 were selected, Nivolumab improved the OS and PFS remarkably by 26% and 25% when compared with control agents, respectively. However, Pembrolizumab significantly increased the rate of disease progression by 47% relative to the control medications. CONCLUSION Among patients suffering from gastric cancer, considering PD-L1 CPS thresholds seems to be a more reliable predictive factor than TPS threshold for lower rate of mortality when PD-1/PD-L1 inhibitors are administered.
Collapse
Affiliation(s)
- Maryam Noori
- Student Research Committee, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Farimah Fayyaz
- Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
- Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Davood Bashash
- School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
11
|
Jiang Q, Liu W, Zeng X, Zhang C, Du Y, Zeng L, Yin Y, Fan J, Yang M, Tao K, Zhang P. Safety and efficacy of tislelizumab plus chemotherapy versus chemotherapy alone as neoadjuvant treatment for patients with locally advanced gastric cancer: real-world experience with a consecutive patient cohort. Front Immunol 2023; 14:1122121. [PMID: 37215127 PMCID: PMC10195027 DOI: 10.3389/fimmu.2023.1122121] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Accepted: 04/18/2023] [Indexed: 05/24/2023] Open
Abstract
Objectives Immunotherapy plus chemotherapy has recently been applied in the neoadjuvant treatment for locally advanced gastric cancer (LAGC), while its superiority over neoadjuvant chemotherapy (NACT) alone remains to be explored. This study explored the safety and efficacy of NACT plus tislelizumab in patients with LAGC. Methods The data on patients with LAGC who received NACT combined with radical gastrectomy and NACT plus tislelizumab followed by radical gastrectomy was retrospectively collected. Clinicopathological characteristics of the two groups were compared. Results A total of 119 and 50 patients with gastric cancer treated with NACT and NACT plus tislelizumab, respectively, were enrolled. No significant difference was found between the baseline data of the two groups. The operative time (210.5 ± 70.4 min vs. 237.6 ± 68.4 min, P=0.732), intraoperative blood loss (157.8 ± 75.9 ml vs. 149.1 ± 92.5 ml, P=0.609), and number of dissected lymph nodes (24.7 ± 9.3 vs. 28.1 ± 10.3, P=0.195) was not statistically different between the two groups. In comparison to the NACT plus tislelizumab group, the R0 resection rate (100% vs. 89.9%, P=0.019) and pathologic complete response rate (26.0% vs. 3.4%, P<0.001) were significantly lower in the NACT group. The postoperative complication rates were 24.4% and 26.0% in the NACT and NACT plus tislelizumab groups with no significant difference (P=0.823). In subgroup analysis, tumor regression grade (TRG) (TRG 3: 72.3% vs. 23.5%, P<0.001) and ypN stage (stages 2-3: 46.8% vs. 5.9%, P=0.003) in the NACT group were significantly higher compared with the NACT plus tislelizumab group in esophagogastric junction carcinoma. Conclusion Compared with the S-1 and oxaliplatin (SOX) or 5-fluorouracil, folinic acid, and oxaliplatin (FOLFOX) NACT regimen, NACT plus tislelizumab significantly improved the efficacy and R0 resection rate of LAGC without increasing the incidence of perioperative complications, particularly in esophagogastric junction carcinoma.
Collapse
Affiliation(s)
- Qi Jiang
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Weizhen Liu
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Xiangyu Zeng
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Chenggang Zhang
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yuqiang Du
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Liwu Zeng
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Yuping Yin
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Jun Fan
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Ming Yang
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Kaixiong Tao
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Peng Zhang
- Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| |
Collapse
|
|
12
|
Jiang H, Wang J, Deng W. Pathologic complete response to chemoimmunotherapy of an advanced gastric cancer patient with high PD-L1 expression, dMMR, and unique gut microbiota composition: A case report. Front Oncol 2023; 13:1150931. [PMID: 37007083 PMCID: PMC10061119 DOI: 10.3389/fonc.2023.1150931] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Accepted: 03/03/2023] [Indexed: 03/18/2023] Open
Abstract
BackgroundAdvanced gastric cancer (AGC) is a malignant disease with limited therapeutic options and a poor prognosis. Recently, immune checkpoint inhibitors (ICIs), represented by inhibitors of programmed cell death 1 (PD-1)/programmed death-ligand 1 (PD-L1), have emerged as a potential gastric cancer (GC) therapy.Case presentationThis case study aimed to reveal the tumor response to neoadjuvant chemotherapy combined with camrelizumab in a patient with AGC based on the characteristics of the clinical pathology, genomics variation, and gut microbiome. Samples from a 59-year-old male patient diagnosed with locally advanced unresectable GC (cT4bN2M0, high grade) presenting PD-L1-positive, deficient mismatch repair (dMMR), and highly specific gut microbiota enrichment were subjected to target region sequencing, metagenomic sequencing, and immunohistochemistry staining. The patient received neoadjuvant therapy, including camrelizumab, apatinib, S-1, and abraxane, which eventually promoted dramatic tumor shrinkage without serious adverse effects and allowed subsequent radical gastrectomy and lymphadenectomy. Finally, the patient achieved pathologic complete response (pCR), and the recurrence-free survival time was 19 months at the last follow-up in April 2021.ConclusionsThe patient with PD-L1-positive, dMMR, and a highly specific gut microbiota enrichment exhibited a pCR to neoadjuvant chemoimmunotherapy.
Collapse
Affiliation(s)
- Hongpeng Jiang
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University & National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Junyun Wang
- CAS Key Laboratory of Genome Sciences and Information, Beijing Institute of Genomics, Chinese Academy of Sciences/China National Center for Bioinformation, Beijing, China
| | - Wei Deng
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University & National Clinical Research Center for Digestive Diseases, Beijing, China
- *Correspondence: Wei Deng,
| |
Collapse
|
|
13
|
Identification of Immunogenic Cell-Death-Related Subtypes and Development of a Prognostic Signature in Gastric Cancer. Biomolecules 2023; 13:biom13030528. [PMID: 36979463 PMCID: PMC10046021 DOI: 10.3390/biom13030528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 03/06/2023] [Accepted: 03/07/2023] [Indexed: 03/17/2023] Open
Abstract
Background: Immunogenic cell death (ICD) is considered a promising type of regulated cell death and exerts effects by activating the adaptive immune response, reshaping the tumor environment (TME) and improving therapeutic efficacy. However, the potential roles and prognostic value of ICD-associated genes in gastric cancer (GC) remain unclear. Methods: The RNA expression data and clinical information of 1090 GC patients from six cohorts were collected. Consensus clustering was used to identify three distinct molecular subtypes. Then, a robust prognostic ICD_score for predicting prognosis was built via WGCNA and LASSO Cox regression according to the TCGA cohort, and the predictive capability of the ICD_score in GC patients was validated in the other cohorts. ICD-related immune features were analyzed using a CIBERSORT method and verified by immunofluorescence. Results: We found that ICD-related gene variations were correlated with clinical outcomes, tumor immune microenvironment (TIME) characteristics and treatment response. We then constructed an ICD signature that classifies cases as low- and high-ICD_score groups. The high-ICD_score group indicates unfavorable OS, a more advanced TNM stage, and presents an immune-suppressed phenotype, which has more infiltrations of pro-tumor immune cells, such as macrophages, which was verified by immunofluorescence. In addition, a nomogram containing the ICD_score showed a high predictive accuracy with AUCs of 0.715, 0.731 and 0.8 on Years 1, 3, and 5. Conclusion: We performed the first and synthesis ICD analysis in GC and built a clinical application tool based on the ICD signature, which paved a new path for assessing prognosis and guiding individual treatment.
Collapse
|
|
14
|
Satake H, Lee KW, Chung HC, Lee J, Yamaguchi K, Chen JS, Yoshikawa T, Amagai K, Yeh KH, Goto M, Chao Y, Lam KO, Han SR, Shiratori S, Shah S, Shitara K. Pembrolizumab or pembrolizumab plus chemotherapy versus standard of care chemotherapy in patients with advanced gastric or gastroesophageal junction adenocarcinoma: Asian subgroup analysis of KEYNOTE-062. Jpn J Clin Oncol 2023; 53:221-229. [PMID: 36533429 PMCID: PMC9991501 DOI: 10.1093/jjco/hyac188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Accepted: 11/15/2022] [Indexed: 12/23/2022] Open
Abstract
OBJECTIVE First-line pembrolizumab with/without chemotherapy versus chemotherapy was evaluated in programmed death ligand 1 combined positive score ≥1, locally advanced/unresectable or metastatic gastric cancer/gastrooesophageal junction cancer in the KEYNOTE-062 study. We present results for patients enrolled in Asia. METHODS Eligible patients were randomly assigned 1:1:1 to pembrolizumab 200 mg, pembrolizumab plus chemotherapy (cisplatin + 5-fluorouracil or capecitabine) or placebo plus chemotherapy Q3W. End points included overall survival (primary) in combined positive score ≥1 and combined positive score ≥10 populations and safety and tolerability (secondary). RESULTS A total of 187 patients were enrolled in Asia (pembrolizumab, n = 62; pembrolizumab plus chemotherapy, n = 64; chemotherapy, n = 61). Compared with the global population, higher proportions of patients had Eastern Cooperative Oncology Group performance status 0 and a diagnosis of stomach cancer. In the programmed death ligand 1 combined positive score ≥1 population, median overall survival was numerically longer with pembrolizumab versus chemotherapy (22.7 vs 13.8 months; hazard ratio, 0.54; 95% confidence interval, 0.35-0.82) and pembrolizumab plus chemotherapy versus chemotherapy (16.5 vs 13.8 months; hazard ratio, 0.78; 95% confidence interval, 0.53-1.16). In the programmed death ligand 1 combined positive score ≥10 population, median overall survival was also numerically longer with pembrolizumab versus chemotherapy (28.5 vs 14.8 months; hazard ratio, 0.43; 95% confidence interval, 0.21-0.89) and pembrolizumab plus chemotherapy versus chemotherapy (17.5 vs 14.8 months; hazard ratio, 0.86; 95% confidence interval, 0.45-1.64). The grade 3-5 treatment-related adverse event rate was 19.4%, 75.8% and 64.9% for patients receiving pembrolizumab, pembrolizumab plus chemotherapy and chemotherapy, respectively. CONCLUSIONS This post hoc analysis showed pembrolizumab monotherapy was associated with numerically improved overall survival and a favourable tolerability profile versus chemotherapy in Asians with programmed death ligand 1-positive advanced gastric cancer/gastrooesophageal junction cancer.This study is registered with ClinicalTrials.gov, NCT02494583.
Collapse
Affiliation(s)
- Hironaga Satake
- Department of Medical Oncology, Kobe City Medical Center General Hospital, Kobe City, Japan and Department of Medical Oncology, Kochi Medical School, Kochi, Japan
| | - Keun-Wook Lee
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Hyun Cheol Chung
- Department of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea
| | - Jeeyun Lee
- Division of Hematology/Oncology, Samsung Medical Center Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Kensei Yamaguchi
- Department of Gastroenterological Chemotherapy, The Cancer Institute Hospital of JFCR, Tokyo, Japan
| | - Jen-Shi Chen
- Division of Hematology-Oncology, Chang Gung Memorial Hospital, Tao-Yuan, Taiwan and College of Medicine, Chang Gung University, Tao-Yuan, Taiwan
| | - Takaki Yoshikawa
- Department of Gastric Surgery, National Cancer Center Hospital, Tokyo, Japan
| | - Kenji Amagai
- Department of Gastroenterology, Ibaraki Prefectural Central Hospital, Ibaraki, Japan
| | - Kun-Huei Yeh
- Department of Oncology, National Taiwan University Hospital and Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Masahiro Goto
- Cancer Chemotherapy Center, Osaka Medical and Pharmaceutical University Hospital, Osaka, Japan
| | - Yee Chao
- Department of Oncology, Taipei Veterans General Hospital, Taipei City, Taiwan
| | - Ka-On Lam
- Department of Clinical Oncology, LKS Faculty of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong
| | - Shi Rong Han
- Department of Medical Oncology, MSD K.K., Tokyo, Japan
| | | | - Sukrut Shah
- Department of Medical Oncology, Merck & Co., Inc., Rahway, NJ, USA
| | - Kohei Shitara
- Department of Gastrointestinal Oncology, National Cancer Center Hospital, Kashiwa, Japan.,Department of Immunology, Nagoya University Graduate School of Medicine, Nagoya, Japan
| |
Collapse
|
|
15
|
Zhang L, Wang W, Ge S, Li H, Bai M, Duan J, Yang Y, Ning T, Liu R, Wang X, Ji Z, Wang F, Zhang H, Ba Y, Deng T. Sintilimab Plus Apatinib and Chemotherapy as Second‑/Third-Line treatment for Advanced Gastric or Gastroesophageal Junction Adenocarcinoma: a prospective, Single-Arm, phase II trial. BMC Cancer 2023; 23:211. [PMID: 36872337 PMCID: PMC9985926 DOI: 10.1186/s12885-023-10661-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Accepted: 02/20/2023] [Indexed: 03/07/2023] Open
Abstract
BACKGROUND The prognosis of patients with previously treated advanced gastric or gastroesophageal junction (GEJ) cancer remains poor. Given the robust development of immunotherapy and targeted therapy during the last decades, we aimed to investigate if the combination of traditional second-line chemotherapy with sintilimab and apatinib could bring survival benefits for these patients. METHODS In this single-center, single-arm, phase II trial, patients with previously treated advanced gastric or GEJ adenocarcinoma received specific dose level of intravenous paclitaxel or irinotecan (investigator's choice), 200 mg intravenous sintilimab on day 1, and 250 mg oral apatinib once daily continuously in each cycle until disease progression, intolerable toxicity, or withdrawal of consent. The primary endpoints were objective response rate and progression-free survival. The secondary endpoints were mainly overall survival and safety. RESULTS From May 2019 to May 2021, 30 patients were enrolled. At the data cutoff date (March 19, 2022), the median follow-up duration was 12.3 months and 53.6% (95% CI, 33.9-72.5%) patients achieved objective response. The median progression-free survival and overall survival were 8.5 months (95% CI, 5.4-11.5) and 12.5 months (95% CI, 3.7-21.3), respectively. Grade 3-4 adverse events included hematological toxicities, elevated alanine aminotransferase, elevated aspartate aminotransferase, elevated alkaline phosphatase, elevated gamma-glutamyl transpeptidase, hyperbilirubinemia and proteinuria. The most frequent grade 3-4 adverse event was neutropenia (13.3%). No serious treatment-related adverse events or treatment-related deaths occurred. CONCLUSION Sintilimab plus apatinib and chemotherapy demonstrates promising anti-tumor activity with manageable safety profile in patients with previously treated advanced gastric or GEJ cancer. TRIAL REGISTRATION ClinicalTrials.gov: NCT05025033, 27/08/2021.
Collapse
Affiliation(s)
- Le Zhang
- Department of GI Medical Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, 300060, Tianjin, China
| | - Weixue Wang
- Department of GI Medical Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, 300060, Tianjin, China
| | - Shaohua Ge
- Department of GI Medical Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, 300060, Tianjin, China
| | - Hongli Li
- Department of GI Medical Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, 300060, Tianjin, China
| | - Ming Bai
- Department of GI Medical Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, 300060, Tianjin, China
| | - Jingjing Duan
- Department of GI Medical Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, 300060, Tianjin, China
| | - Yuchong Yang
- Department of GI Medical Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, 300060, Tianjin, China
| | - Tao Ning
- Department of GI Medical Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, 300060, Tianjin, China
| | - Rui Liu
- Department of GI Medical Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, 300060, Tianjin, China
| | - Xia Wang
- Department of GI Medical Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, 300060, Tianjin, China
| | - Zhi Ji
- Department of GI Medical Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, 300060, Tianjin, China
| | - Feixue Wang
- Department of GI Medical Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, 300060, Tianjin, China
| | - Haiyang Zhang
- Department of GI Medical Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, 300060, Tianjin, China
| | - Yi Ba
- Department of GI Medical Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, 300060, Tianjin, China.
| | - Ting Deng
- Department of GI Medical Oncology, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, 300060, Tianjin, China.
| |
Collapse
|
|
16
|
Liu T, Bai Y, Lin X, Li W, Wang J, Zhang X, Pan H, Bai C, Bai L, Cheng Y, Zhang J, Zhong H, Ba Y, Hu W, Xu R, Guo W, Qin S, Yang N, Lu J, Shitara K, Lei M, Li M, Bao N, Chen T, Shen L. First-line nivolumab plus chemotherapy vs chemotherapy in patients with advanced gastric, gastroesophageal junction and esophageal adenocarcinoma: CheckMate 649 Chinese subgroup analysis. Int J Cancer 2023; 152:749-760. [PMID: 36121651 PMCID: PMC10092493 DOI: 10.1002/ijc.34296] [Citation(s) in RCA: 48] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Revised: 07/13/2022] [Accepted: 08/05/2022] [Indexed: 02/01/2023]
Abstract
First-line chemotherapy for advanced/metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric/gastroesophageal junction cancer (GC/GEJC) has poor median overall survival (OS; <1 year). We report efficacy and safety results from Chinese patients in the phase III global CheckMate 649 study of nivolumab plus chemotherapy vs chemotherapy for the first-line treatment of GC/GEJC/esophageal adenocarcinoma (EAC). Chinese patients with previously untreated advanced or metastatic GC/GEJC/EAC were randomized to receive nivolumab (360 mg Q3W or 240 mg Q2W) plus chemotherapy (XELOX [capecitabine and oxaliplatin] Q3W or FOLFOX [oxaliplatin, leucovorin and 5-fluorouracil] Q2W), nivolumab plus ipilimumab (not reported) or chemotherapy alone. OS, blinded independent central review-assessed progression-free survival (PFS), objective response rate (ORR), duration of response (DOR) and safety are reported. Of 1581 patients enrolled and randomized, 208 were Chinese. In these patients, nivolumab plus chemotherapy resulted in clinically meaningful improvement in median OS (14.3 vs 10.2 months; HR 0.61 [95% CI: 0.44-0.85]), median PFS (8.3 vs 5.6 months; HR 0.57 [95% CI: 0.40-0.80]), ORR (66% vs 45%) and median DOR (12.2 vs 5.6 months) vs chemotherapy, respectively. The safety profile was acceptable, with no new safety signals observed. Consistent with results from the global primary analysis of CheckMate 649, nivolumab plus chemotherapy demonstrated a clinically meaningful improvement in OS and PFS and higher response rate vs chemotherapy and an acceptable safety profile in Chinese patients. Nivolumab plus chemotherapy represents a new standard first-line treatment for Chinese patients with non-HER2-positive advanced GC/GEJC/EAC.
Collapse
Affiliation(s)
- Tianshu Liu
- Zhongshan Hospital Fudan University, Shanghai, China
| | - Yuxian Bai
- Herbin Medical University, Heilongjiang, China
| | - Xiaoyan Lin
- Fujian Medical University Union Hospital, Fuzhou, China
| | - Wei Li
- The First Hospital of Jilin University, Changchun, China
| | - Jufeng Wang
- The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
| | - Xiaochun Zhang
- The Affiliated Hospital of Qingdao University, Qingdao, China
| | | | - Chunmei Bai
- Peking Union Medical College Hospital, Beijing, China
| | - Li Bai
- China P.L.A. General Hospital (301 Hospital), Beijing, China
| | | | | | | | - Yi Ba
- Tianjin Medical University Cancer Institute and Hospital, Tianjin, China
| | - Wenwei Hu
- The First People's Hospital of Changzhou, Changzhou, China
| | - Ruihua Xu
- Medical Oncology Cancer Center, Sun Yat-Sen University, Guangzhou, China
| | - Weijian Guo
- Fudan University Shanghai Cancer Center, Shanghai, China
| | - Shukui Qin
- Eastern Theater General Hospital, QinHuai District Medical Area, China
| | - Nong Yang
- Hunan Cancer Hospital, Changsha Shi, China
| | | | - Kohei Shitara
- National Cancer Center Hospital East, Kashiwa, Japan
| | - Ming Lei
- Bristol Myers Squibb, Princeton, New Jersey, USA
| | - Mingshun Li
- Bristol Myers Squibb, Princeton, New Jersey, USA
| | - Nicole Bao
- Bristol Myers Squibb, Princeton, New Jersey, USA
| | - Tian Chen
- Bristol Myers Squibb, Princeton, New Jersey, USA
| | - Lin Shen
- Department of Gastrointestinal Oncology Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China
| |
Collapse
|
|
17
|
Wang H, Xu Y, Zuo F, Liu J, Yang J. Immune-based combination therapy for esophageal cancer. Front Immunol 2022; 13:1020290. [PMID: 36591219 PMCID: PMC9797857 DOI: 10.3389/fimmu.2022.1020290] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Accepted: 11/30/2022] [Indexed: 12/23/2022] Open
Abstract
Esophageal cancer (EC) is an aggressive malignancy raising a healthcare concern worldwide. Standard treatment options include surgical resection, chemotherapy, radiation therapy, and targeted molecular therapy. The five-year survival rate for all stages of EC is approximately 20%, ranging from 5% to 47%, with a high recurrence rate and poor prognosis after treatment. Immunotherapy has shown better efficacy and tolerance than conventional therapies for several malignancies. Immunotherapy of EC, including immune checkpoint inhibitors, cancer vaccines, and adoptive cell therapy, has shown clinical advantages. In particular, monoclonal antibodies against PD-1 have a satisfactory role in combination therapy and are recommended for first- or second-line treatments. Here, we present a systematic summary and analysis of immunotherapy-based combination therapies for EC.
Collapse
Affiliation(s)
- Huiling Wang
- Laboratory of Integrative Medicine, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, China
| | - Yufei Xu
- Laboratory of Integrative Medicine, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, China
| | - Fengli Zuo
- Laboratory of Integrative Medicine, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, China
| | - Junzhi Liu
- West China School of Medicine, West China Hospital of Sichuan University, Chengdu, China
| | - Jiqiao Yang
- Laboratory of Integrative Medicine, Clinical Research Center for Breast, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center, Chengdu, China,Breast Center, West China Hospital of Sichuan University, Chengdu, China,*Correspondence: Jiqiao Yang,
| |
Collapse
|
|
18
|
Zheng J, Huang B, Xiao L, Wu M, Li J. Treatment- and immune-related adverse events of immune checkpoint inhibitors in esophageal or gastroesophageal junction cancer: A network meta-analysis of randomized controlled trials. Front Oncol 2022; 12:821626. [PMID: 36568203 PMCID: PMC9780048 DOI: 10.3389/fonc.2022.821626] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Accepted: 11/14/2022] [Indexed: 12/13/2022] Open
Abstract
Objective To systematically evaluate the safety and adverse event profiles of immune checkpoint inhibitors (ICIs) in patients with esophageal cancer (EPC) or gastroesophageal junction cancer (GEJC). Methods PubMed, Web of Science, Cochrane Library, and major conference proceedings were systematically searched for all phase II or phase III randomized controlled trials (RCTs) in EPC or GEJC using ICIs. Safety outcomes including treatment-related adverse events (trAEs), immune-related adverse events (irAEs), and serious trAEs were evaluated by network meta-analysis or dichotomous meta-analysis based on the random-effects model. Results Eleven RCTs involving EPC (five RCTs) and GEJC (six RCTs) were included in the final meta-analysis. NMA showed that placebo was associated with the best safety ranking for grade 3-5 trAEs (SUCRA = 96.0%), followed by avelumab (78.6%), nivolumab (73.9%), ipilimumab (57.0%), and pembrolizumab (56.6%). Conventional pairwise meta-analysis (CPM) showed that ICIs have similar grade 3-5 trAE risk compared with chemotherapy (RR = 0.764, 95% CI: 0.574 to 1.016, I 2 = 95.7%, Z = 1.85, P = 0.065). NMA showed that the general safety of grade 3-5 irAEs ranked from high to low is as follows: ChT (85.1%), placebo (76.5%), ipilimumab (56.0%), nivolumab (48.5%), avelumab (48.4%), camrelizumab (41.8%), pembrolizumab (36.4%), and nivolumab + ipilimumab (21.6%). CPM showed that the rates of grade 3-5 irAEs in the ICI group and the chemotherapy group were 7.35% (154/2,095, 95% CI: [6.23%, 8.47%]) versus 2.25% (42/1,869, 95% CI: [1.58%, 2.92%]), with statistical significance (RR = 3.151, 95% CI = 2.175 to 4.563, Z = 6.07, P = 0.000). The most common irAEs in the ICI group were skin reaction (15.76%, 95% CI: [13.67%, 17.84%]), followed by hypothyroidism (9.73%, 95% CI: [8.07%, 11.39%]), infusion-related reactions (5.93%, 95% CI: [4.29%, 7.58%]), hepatitis (5.25%, 95% CI: [4.28%, 6.22%]), and pneumonitis (4.45%, 95% CI: [3.5%, 5.4%]). Conclusion Different ICIs had different toxicity manifestations and should not be considered as an entity. Compared with chemotherapy, ICIs were more prone to irAEs, but the overall rates remained low and acceptable. For clinicians, it is important to recognize and monitor the adverse events caused by ICIs for patients with EPC or GEJC.
Collapse
Affiliation(s)
- Jianqing Zheng
- Department of Radiation Oncology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China,*Correspondence: Jiancheng Li, ; Jianqing Zheng,
| | - Bifen Huang
- Department of Obstetrics and Gynecology, Quanzhou Medical College People’s Hospital Affiliated, Quanzhou, China
| | - Lihua Xiao
- Department of Radiation Oncology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Min Wu
- Department of Radiation Oncology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Jiancheng Li
- Department of Radiation Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China,*Correspondence: Jiancheng Li, ; Jianqing Zheng,
| |
Collapse
|
|
19
|
Cabeza-Segura M, Gambardella V, Gimeno-Valiente F, Carbonell-Asins JA, Alarcón-Molero L, González-Vilanova A, Zuñiga-Trejos S, Rentero-Garrido P, Villagrasa R, Gil M, Durá A, Richart P, Alonso N, Huerta M, Roselló S, Roda D, Tarazona N, Martínez-Ciarpaglini C, Castillo J, Cervantes A, Fleitas T. Integrative immune transcriptomic classification improves patient selection for precision immunotherapy in advanced gastro-oesophageal adenocarcinoma. Br J Cancer 2022; 127:2198-2206. [PMID: 36253523 PMCID: PMC9727124 DOI: 10.1038/s41416-022-02005-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 09/18/2022] [Accepted: 09/27/2022] [Indexed: 01/29/2023] Open
Abstract
BACKGROUND Advanced gastro-oesophageal cancer (GEA) treatment has been improved by the introduction of immune checkpoint inhibitors (CPIs), yet identifying predictive biomarkers remains a priority, particularly in patients with a combined positive score (CPS) < 5, where the benefit is less clear. Our study assesses certain immune microenvironment features related to sensitivity or resistance to CPIs with the aim of implementing a personalised approach across CPS < 5 GEA. DESIGN Through integrative transcriptomic and clinicopathological analyses, we studied in both a retrospective and a prospective cohort, the immune tumour microenvironment features. We analysed the cell types composing the immune infiltrate highlighting their functional activity. RESULTS This integrative study allowed the identification of four different groups across our patients. Among them, we identified a cluster whose tumours expressed the most gene signatures related to immunomodulatory pathways and immunotherapy response. These tumours presented an enriched immune infiltrate showing high immune function activity that could potentially achieve the best benefit from CPIs. Finally, our findings were proven in an external CPI-exposed population, where the use of our transcriptomic results combined with CPS helped better identify those patients who could benefit from immunotherapy than using CPS alone (p = 0.043). CONCLUSIONS This transcriptomic classification could improve precision immunotherapy for GEA.
Collapse
Affiliation(s)
- Manuel Cabeza-Segura
- grid.5338.d0000 0001 2173 938XDepartment of Medical Oncology, Hospital Clínico Universitario, INCLIVA, Biomedical Research Institute, University of Valencia, Valencia, Spain
| | - Valentina Gambardella
- grid.5338.d0000 0001 2173 938XDepartment of Medical Oncology, Hospital Clínico Universitario, INCLIVA, Biomedical Research Institute, University of Valencia, Valencia, Spain ,grid.510933.d0000 0004 8339 0058CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
| | - Francisco Gimeno-Valiente
- grid.5338.d0000 0001 2173 938XDepartment of Medical Oncology, Hospital Clínico Universitario, INCLIVA, Biomedical Research Institute, University of Valencia, Valencia, Spain ,grid.83440.3b0000000121901201Cancer Evolution and Genome Instability Laboratory, UCL Cancer Institute, London, UK
| | - Juan Antonio Carbonell-Asins
- grid.429003.c0000 0004 7413 8491Department of Bioinformatics and Biostatistics. INCLIVA, Biomedical Research Institute, Valencia, Spain
| | - Lorena Alarcón-Molero
- grid.5338.d0000 0001 2173 938XDepartment of Pathology, INCLIVA, Biomedical Research Institute, University of Valencia, Valencia, Spain
| | - Arturo González-Vilanova
- grid.429003.c0000 0004 7413 8491Department of Bioinformatics and Biostatistics. INCLIVA, Biomedical Research Institute, Valencia, Spain
| | - Sheila Zuñiga-Trejos
- grid.429003.c0000 0004 7413 8491Department of Bioinformatics and Biostatistics. INCLIVA, Biomedical Research Institute, Valencia, Spain
| | - Pilar Rentero-Garrido
- grid.429003.c0000 0004 7413 8491Department of Precision Medicine, INCLIVA, Biomedical Research Institute, Valencia, Spain
| | - Rosana Villagrasa
- grid.411308.fDepartment of Gastroenterology and Hepatology, Hospital Clínico Universitario de Valencia, Valencia, Spain
| | - Mireia Gil
- grid.106023.60000 0004 1770 977XDepartment of Medical Oncology, Hospital General Universitario, Valencia, Spain
| | - Ana Durá
- grid.106023.60000 0004 1770 977XDepartment of Gastroenterology and Hepatology, Hospital General Universitario, Valencia, Spain
| | - Paula Richart
- grid.84393.350000 0001 0360 9602Department of Medical Oncology, Hospital Universitario y Politécnico La Fe, Valencia, Spain
| | - Noelia Alonso
- grid.84393.350000 0001 0360 9602Department of Gastroenterology and Hepatology, Hospital Universitario y Politécnico La Fe, Valencia, Spain
| | - Marisol Huerta
- grid.5338.d0000 0001 2173 938XDepartment of Medical Oncology, Hospital Clínico Universitario, INCLIVA, Biomedical Research Institute, University of Valencia, Valencia, Spain
| | - Susana Roselló
- grid.5338.d0000 0001 2173 938XDepartment of Medical Oncology, Hospital Clínico Universitario, INCLIVA, Biomedical Research Institute, University of Valencia, Valencia, Spain ,grid.510933.d0000 0004 8339 0058CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
| | - Desamparados Roda
- grid.5338.d0000 0001 2173 938XDepartment of Medical Oncology, Hospital Clínico Universitario, INCLIVA, Biomedical Research Institute, University of Valencia, Valencia, Spain ,grid.510933.d0000 0004 8339 0058CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
| | - Noelia Tarazona
- grid.5338.d0000 0001 2173 938XDepartment of Medical Oncology, Hospital Clínico Universitario, INCLIVA, Biomedical Research Institute, University of Valencia, Valencia, Spain ,grid.510933.d0000 0004 8339 0058CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
| | - Carolina Martínez-Ciarpaglini
- grid.510933.d0000 0004 8339 0058CIBERONC, Instituto de Salud Carlos III, Madrid, Spain ,grid.5338.d0000 0001 2173 938XDepartment of Pathology, INCLIVA, Biomedical Research Institute, University of Valencia, Valencia, Spain
| | - Josefa Castillo
- grid.5338.d0000 0001 2173 938XDepartment of Medical Oncology, Hospital Clínico Universitario, INCLIVA, Biomedical Research Institute, University of Valencia, Valencia, Spain ,grid.510933.d0000 0004 8339 0058CIBERONC, Instituto de Salud Carlos III, Madrid, Spain ,grid.5338.d0000 0001 2173 938XDepartment of Biochemistry and Molecular Biology, University of Valencia, Valencia, Spain
| | - Andrés Cervantes
- grid.5338.d0000 0001 2173 938XDepartment of Medical Oncology, Hospital Clínico Universitario, INCLIVA, Biomedical Research Institute, University of Valencia, Valencia, Spain ,grid.510933.d0000 0004 8339 0058CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
| | - Tania Fleitas
- grid.5338.d0000 0001 2173 938XDepartment of Medical Oncology, Hospital Clínico Universitario, INCLIVA, Biomedical Research Institute, University of Valencia, Valencia, Spain ,grid.510933.d0000 0004 8339 0058CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
| |
Collapse
|
|
20
|
Gou M, Zhang Y. Pretreatment platelet-to-lymphocyte ratio (PLR) as a prognosticating indicator for gastric cancer patients receiving immunotherapy. Discov Oncol 2022; 13:118. [PMID: 36326905 PMCID: PMC9633881 DOI: 10.1007/s12672-022-00571-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 09/27/2022] [Indexed: 11/06/2022] Open
Abstract
BACKGROUND Previous investigations suggest that systemic inflammation markers are able to provide prognostic value in several cancers. This study seeks to characterize the ability of pretreatment platelet-to-lymphocyte ratio (PLR) to prognosticate advanced or metastatic gastric cancer patients (AGC or MGC, respectively) receiving immunotherapy. METHODS AGC and MGC patients exposed to PD-1 inhibitors from January 2016-August 2021 in the Chinese PLA General Hospital were recruited. Correlations between PLR and overall survival (OS), progression-free survival (PFS), and immunotherapy-associated tumor response rates were determined. RESULTS 237 patients were enrolled for this retrospective investigation. The 6 month and 12 month PFS based on the area under the curve value was 0.60 and 0.65 (p < 0.05). based on a calculated PLR cut-off value of 139.41, The PLR < 139.41 group has a longer OS in contrast with the PLR ≥ 139.41 group (13.46 m vs 10.71 m, HR = 0.57, 95% CI 0.42-0.78, p = 0.004). The PLR < 139.41 group had a PFS of 7.93 m in contrast to the 4.75 m seen in those with PLR ≥ 139.41 group (HR = 0.57, 95% CI 0.43-0.76, p = 0.002). The disease control rate (DCR) and objective response rate (ORR) were 86.17% and 30.85%, respectively, in the PLR < 139.41 group, but were 82.52% and 32.17%, respectively in the PLR ≥ 139.41 group. Both groups did not show any marked differences in terms of ORR and DCR (p = 0.887, p = 0.476). PLR is an independent prognostic indicator for OS and PFS upon uni- and multivariate analyses (p < 0.05). CONCLUSIONS Pre-treatment PLR correlated significantly with PFS and OS in AGC and MGC patients who received immunotherapy. An elevated PLR may provide guidance on subsequent treatment options.
Collapse
Affiliation(s)
- Miaomiao Gou
- Medical Oncology Department, The Fifth Medical Center, Chinese PLA General Hospital, Beijing, People’s Republic of China
| | - Yong Zhang
- Medical Oncology Department, The Second Medical Center, Chinese PLA General Hospital, Fuxing road 28, Haidian district, Beijing, 100853 People’s Republic of China
| |
Collapse
|
|
21
|
Zeng Y, Jin RU. Molecular pathogenesis, targeted therapies, and future perspectives for gastric cancer. Semin Cancer Biol 2022; 86:566-582. [PMID: 34933124 DOI: 10.1016/j.semcancer.2021.12.004] [Citation(s) in RCA: 93] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 11/29/2021] [Accepted: 12/11/2021] [Indexed: 01/27/2023]
Abstract
Gastric cancer is a major source of global cancer mortality with limited treatment options and poor patient survival. As our molecular understanding of gastric cancer improves, we are now beginning to recognize that these cancers are a heterogeneous group of diseases with incredibly unique pathogeneses and active oncogenic pathways. It is this molecular diversity and oftentimes lack of common oncogenic driver mutations that bestow the poor treatment responses that oncologists often face when treating gastric cancer. In this review, we will examine the treatments for gastric cancer including up-to-date molecularly targeted therapies and immunotherapies. We will then review the molecular subtypes of gastric cancer to highlight the diversity seen in this disease. We will then shift our discussion to basic science and gastric cancer mouse models as tools to study gastric cancer molecular heterogeneity. Furthermore, we will elaborate on a molecular process termed paligenosis and the cyclical hit model as key events during gastric cancer initiation that impart nondividing mature differentiated cells the ability to re-enter the cell cycle and accumulate disparate genomic mutations during years of chronic inflammation and injury. As our basic science understanding of gastric cancer advances, so too must our translational and clinical efforts. We will end with a discussion regarding single-cell molecular analyses and cancer organoid technologies as future translational avenues to advance our understanding of gastric cancer heterogeneity and to design precision-based gastric cancer treatments. Elucidation of interpatient and intratumor heterogeneity is the only way to advance future cancer prevention, diagnoses and treatment.
Collapse
Affiliation(s)
- Yongji Zeng
- Section of Gastroenterology, Department of Medicine, Baylor College of Medicine, Houston, USA
| | - Ramon U Jin
- Section of Hematology/Oncology, Department of Medicine, Baylor College of Medicine, Houston, USA.
| |
Collapse
|
|
22
|
Wan M, Ding Y, Mao C, Ma X, Li N, Xiao C, Qian J, Jiang H, Zheng Y, Wu L, Teng L, Xu N. Association of inflammatory markers with survival in patients with advanced gastric cancer treated with immune checkpoint inhibitors combined with chemotherapy as first line treatment. Front Oncol 2022; 12:1029960. [PMID: 36387183 PMCID: PMC9650180 DOI: 10.3389/fonc.2022.1029960] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Accepted: 10/17/2022] [Indexed: 12/27/2023] Open
Abstract
BACKGROUND The emergence of immune checkpoint inhibitors has changed the landscape of first-line treatment of patients with advanced gastric cancer. Currently, the prognostic significance of inflammatory markers in first-line immunotherapy combined with chemotherapy for gastric cancer is currently unclear. This study aimed to identify inflammatory markers with potential to predict treatment outcome in advanced gastric cancer patients receiving immunotherapy combined with chemotherapy. METHODS This retrospective study enrolled untreated advanced or metastatic gastric or gastro-esophageal junction cancer patients from 5 clinical trials (the clinical trial cohort) and the real world (the real-word cohort). Inflammatory markers included in the analysis included neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), systemic inflammation index (SII), and derived neutrophil-to-lymphocyte ratio (dNLR). Receiver operating characteristic (ROC) curves were constructed to identify optimal cut-off values. The prognostic potential of the markers was determined using Kaplan-Meier analysis, univariate and multivariate Cox-regression analyses in the clinical trial cohort and the findings were validated in the real-world cohort. RESULTS In the clinical trial cohort (n=45), MLR, PLR and SII were associated with PFS but not OS (All P<0.05), while dNLR was not correlated with PFS or OS. Only NLR was associated with PFS and OS and identified as an independent prognostic predictor in the univariate and multivariate analyses. The prognostic value of NLR was validated in the real-world cohort (n=55). CONCLUSIONS NLR was a strong predictor of PFS and OS in patients with advanced gastric cancer receiving immune checkpoint inhibitors combined with chemotherapy. Further prospective studies are required to validate our results.
Collapse
Affiliation(s)
- Mingyu Wan
- Department of Medical Oncology, The First Affiliated Hospital of Zhejiang University, Hangzhou, China
| | - Yongfeng Ding
- Department of Medical Oncology, The First Affiliated Hospital of Zhejiang University, Hangzhou, China
| | - Chenyu Mao
- Department of Medical Oncology, The First Affiliated Hospital of Zhejiang University, Hangzhou, China
| | - Xiaolu Ma
- Department of Medical Oncology, The First Affiliated Hospital of Zhejiang University, Hangzhou, China
| | - Ning Li
- Department of Medical Oncology, The First Affiliated Hospital of Zhejiang University, Hangzhou, China
| | - Cheng Xiao
- Department of Medical Oncology, The First Affiliated Hospital of Zhejiang University, Hangzhou, China
| | - Jiong Qian
- Department of Medical Oncology, The First Affiliated Hospital of Zhejiang University, Hangzhou, China
| | - Haiping Jiang
- Department of Medical Oncology, The First Affiliated Hospital of Zhejiang University, Hangzhou, China
| | - Yulong Zheng
- Department of Medical Oncology, The First Affiliated Hospital of Zhejiang University, Hangzhou, China
| | - Luntao Wu
- Department of Medical Oncology, The First Affiliated Hospital of Zhejiang University, Hangzhou, China
| | - Lisong Teng
- Department of Surgical Oncology, The First Affiliated Hospital of Zhejiang University, Hangzhou, China
| | - Nong Xu
- Department of Medical Oncology, The First Affiliated Hospital of Zhejiang University, Hangzhou, China
| |
Collapse
|
|
23
|
Gou M, Qian N, Zhang Y, Wei L, Fan Q, Wang Z, Dai G. Construction of a nomogram to predict the survival of metastatic gastric cancer patients that received immunotherapy. Front Immunol 2022; 13:950868. [PMID: 36225924 PMCID: PMC9549034 DOI: 10.3389/fimmu.2022.950868] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Accepted: 09/05/2022] [Indexed: 11/13/2022] Open
Abstract
Background Immunotherapy has shown promising results for metastatic gastric cancer (MGC) patients. Nevertheless, not all patients can benefit from anti-PD-1 treatment. Thus, this study aimed to develop and validate a prognostic nomogram for MGC patients that received immunotherapy. Methods Herein, MGC patients treated with anti-PD-1 between 1 October 2016 and 1 June 2022 at two separate Chinese PLA General Hospital centers were enrolled and randomly divided into training and validation sets (186 and 80 patients, respectively). The nomogram was constructed based on a multivariable Cox model using baseline variables from the training cohort. Its predictive accuracy was validated by the validation set. The consistency index (C-index) and calibration plots were used to evaluate the discriminative ability and accuracy of the nomogram. The net benefit of the nomogram was evaluated using decision curve analysis (DCA). Finally, we stratified patients by median total nomogram scores and performed Kaplan–Meier survival analyses. Results We developed the nomogram based on the multivariate analysis of the training cohort, including four parameters: surgery history, treatment line, lung immune prognostic index (LIPI), and platelet-to-lymphocyte ratio (PLR). The C-index of the nomogram was 0.745 in the training set. The calibration curve for 1- and 2-year survival showed good agreement between nomogram predictions and actual observations. In the validation group, the calibration curves demonstrated good performance of the nomogram, with a C-index for overall survival (OS) prediction of 0.713. The OS of patients with a score greater than the median nomogram score was significantly longer than patients with a score lower or equal to the median (p < 0.001). Conclusion We constructed a nomogram to predict the outcomes of MGC patients that received immunotherapy. This nomogram might facilitate individualized survival predictions and be helpful during clinical decision-making for MGC patients under anti-PD-1 therapy.
Collapse
Affiliation(s)
- Miaomiao Gou
- Medical Oncology Department, The Fifth Medical Center, Chinese People’s Liberation Army General Hospital, Beijing, China
| | - Niansong Qian
- Medical Oncology Department, Hainan Medical Center, Chinese People’s Liberation Army General Hospital, Beijing, China
| | - Yong Zhang
- Medical Oncology Department, The Second Medical Center, Chinese People’s Liberation Army General Hospital, Beijing, China
| | - Lihui Wei
- Department of Medicine, Genetron Health (Beijing) Co. Ltd., Beijing, China
| | - Qihuang Fan
- Department of Medicine, Genetron Health (Beijing) Co. Ltd., Beijing, China
| | - Zhikuan Wang
- Medical Oncology Department, The Fifth Medical Center, Chinese People’s Liberation Army General Hospital, Beijing, China
- *Correspondence: Guanghai Dai, ; Zhikuan Wang,
| | - Guanghai Dai
- Medical Oncology Department, The Fifth Medical Center, Chinese People’s Liberation Army General Hospital, Beijing, China
- *Correspondence: Guanghai Dai, ; Zhikuan Wang,
| |
Collapse
|
|
24
|
Zhao S, Su L, Chen Y, Li X, Lin P, Chen W, Fang W, Zhu J, Li H, Ren L, Liu J, Hong Y, Lin S, Fan N, Lin R. Phase 2 randomized controlled trial of intravenous or intraperitoneal paclitaxel plus mFOLFOX6 vs. mFOLFOX6 as first-line treatment of advanced gastric cancer. Front Oncol 2022; 12:850242. [PMID: 36158665 PMCID: PMC9491235 DOI: 10.3389/fonc.2022.850242] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Accepted: 08/09/2022] [Indexed: 11/13/2022] Open
Abstract
Objective We conducted a phase 2 trial to compare the safety and efficacy of intravenous paclitaxel or intraperitoneal paclitaxel plus mFOLFOX6 vs. mFOLFOX6 in untreated advanced gastric cancer. Methods Participants with untreated advanced gastric cancer were randomly assigned (1:1:1) to: intravenous paclitaxel 135 mg/m2 or intraperitoneal paclitaxel 80 mg/m2 plus mFOLFOX6 omitting bolus fluorouracil; or mFOLFOX6 (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, fluorouracil 400 mg/m2 bolus, fluorouracil 2,400 mg/m2 46-h continuous infusion). Treatment was every 14 days for up to 9 cycles followed by S-1 maintenance. The primary outcome was progression-free survival. Results Of 90 enrolled participants, 30 in the intravenous paclitaxel group, 29 in the intraperitoneal paclitaxel group, and 30 in the mFOLFOX6 group were included in the analyses. The median progression-free survival was 6.52, 5.83, and 4.55 months, respectively, for the intravenous paclitaxel group, intraperitoneal paclitaxel group, and mFOLFOX6 group. The hazard ratios were 0.56 (95% CI: 0.33–0.94; p = 0.026) and 0.56 (95% CI: 0.33–0.96; p = 0.037), respectively, for the intravenous paclitaxel group and the intraperitoneal paclitaxel group vs. the mFOLFOX6 group. The most common grade 3/4 adverse events for the intravenous paclitaxel group, intraperitoneal paclitaxel group, and mFOLFOX6 group, respectively, were neutropenia (30.0%, 34.5%, 33.3%), diarrhea (13.3%, 20.7%, 13.3%), and leukopenia (10.0%, 13.8%, 10.0%). No treatment-related death occurred. Conclusion The findings of this phase 2 trial suggest that adding intravenous paclitaxel or intraperitoneal paclitaxel to mFOLFOX6 for untreated advanced gastric cancer improved progression-free survival with manageable adverse events.
Collapse
Affiliation(s)
- Shen Zhao
- Department of Gastrointestinal Medical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
- Fujian Key Laboratory of Translational Cancer Medicine, Fuzhou, China
| | - Liyu Su
- Department of Gastrointestinal Medical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
| | - Yigui Chen
- Department of Gastrointestinal Medical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
| | - Xiaofeng Li
- Department of Medical Oncology, Quanzhou First Hospital, Quanzhou, China
| | - Peicheng Lin
- Department of Radiation Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
| | - Wujin Chen
- Department of Medical Oncology, Affiliated People’s Hospital of Fujian University of Traditional Chinese Medicine, Fuzhou, China
| | - Wenzheng Fang
- Department of Medical Oncology, The 900th Hospital of Joint Logistic Support Force People’s Liberation Army, Fuzhou, China
| | - Jinfeng Zhu
- Department of Medical Oncology, Quanzhou First Hospital, Quanzhou, China
| | - Hui Li
- Department of Gastrointestinal Medical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
| | - Liping Ren
- Department of Medical Oncology, Affiliated People’s Hospital of Fujian University of Traditional Chinese Medicine, Fuzhou, China
| | - Jie Liu
- Department of Gastrointestinal Medical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
| | - Yanni Hong
- Department of Medical Oncology, Quanzhou First Hospital, Quanzhou, China
| | - Shaowei Lin
- School of Public Health, Fujian Medical University, Fuzhou, China
| | - Nanfeng Fan
- Department of Gastrointestinal Medical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
- *Correspondence: Nanfeng Fan, ; Rongbo Lin, linrongbo@fjzlhospital
| | - Rongbo Lin
- Department of Gastrointestinal Medical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, China
- Fujian Key Laboratory of Translational Cancer Medicine, Fuzhou, China
- *Correspondence: Nanfeng Fan, ; Rongbo Lin, linrongbo@fjzlhospital
| |
Collapse
|
|
25
|
Patel MA, Kratz JD, Lubner SJ, Loconte NK, Uboha NV. Esophagogastric Cancers: Integrating Immunotherapy Therapy Into Current Practice. J Clin Oncol 2022; 40:2751-2762. [PMID: 35839430 PMCID: PMC10476757 DOI: 10.1200/jco.21.02500] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Revised: 04/15/2022] [Accepted: 05/18/2022] [Indexed: 12/15/2022] Open
Abstract
Immunotherapy (IO) agents have led to significant improvements in patient outcomes across many tumor types. There have been great efforts to introduce immune checkpoint inhibitors into the treatment paradigm of esophagogastric cancers as well. A number of randomized phase III trials, which will be reviewed here, established the role of these agents in both early-stage and advanced-stage disease. Adjuvant nivolumab is US Food and Drug Administration-approved after neoadjuvant chemoradiation and resection of esophageal and gastroesophageal junction cancers on the basis of the phase III CheckMate 577 trial. In the advanced setting, patients with programmed death receptor ligand-1-positive tumors should be recommended IO in combination with chemotherapy in the first-line setting on the basis of the results from KEYNOTE 590, CheckMate 649, and CheckMate 648. Across trials, chemotherapy continues to play a critical role in the first-line setting and should be offered to all patients who are eligible for systemic therapy, including those with biomarker select tumors. In the later lines of treatment, IO has modest activity, and prior studies have grown largely irrelevant because of the enrollment of IO-naive patients. Similar to other disease types, patients with microsatellite unstable (microsatellite instability high) tumors represent a unique cohort that is more sensitive to IO. However, there are no randomized studies evaluating how best to apply IO in early or advanced stages specifically for the treatment of patients with microsatellite instability high upper GI tumors. Questions remain how to best select patients who benefit from IO treatments, how to augment IO activity in programmed death receptor ligand-1-negative tumors, and how to incorporate IO in late-line settings or for recurrent disease that has been treated with IO-containing regimens during early stages.
Collapse
Affiliation(s)
- Monica A. Patel
- Division of Hematology and Oncology, Department of Medicine, University of Wisconsin, Madison, WI
- Carbone Cancer Center, Madison, WI
| | - Jeremy D. Kratz
- Division of Hematology and Oncology, Department of Medicine, University of Wisconsin, Madison, WI
- Carbone Cancer Center, Madison, WI
| | - Sam J. Lubner
- Division of Hematology and Oncology, Department of Medicine, University of Wisconsin, Madison, WI
- Carbone Cancer Center, Madison, WI
| | - Noelle K. Loconte
- Division of Hematology and Oncology, Department of Medicine, University of Wisconsin, Madison, WI
- Carbone Cancer Center, Madison, WI
| | - Nataliya V. Uboha
- Division of Hematology and Oncology, Department of Medicine, University of Wisconsin, Madison, WI
- Carbone Cancer Center, Madison, WI
| |
Collapse
|
|
26
|
Fong C, Chau I. HER2 Inhibition in Gastric Cancer-Novel Therapeutic Approaches for an Established Target. Cancers (Basel) 2022; 14:cancers14153824. [PMID: 35954487 PMCID: PMC9367333 DOI: 10.3390/cancers14153824] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Revised: 07/27/2022] [Accepted: 08/01/2022] [Indexed: 11/16/2022] Open
Abstract
Gastric cancer is a leading cause of cancer-related deaths globally. Human epidermal growth receptor 2 (HER2) overexpression of HER2 gene amplification is present in 20% of gastric cancers and defines a subset amenable to HER2-directed therapeutics. The seminal ToGA study led to routine use of the monoclonal antibody trastuzumab in conjunction to platinum-fluoropyridimine first-line chemotherapy for HER2-positive gastric cancers as standard-of-care. Although limited progress was made in the decade following ToGA, there is now an abundance of novel therapeutic approaches undergoing investigation in parallel. Additionally, new data from randomised trials have indicated efficacy of the antibody-drug conjugate trastuzumab deruxtecan in chemorefractory patients and increased responses with the addition of first-line immune checkpoint blockade to trastuzumab and chemotherapy. This review will outline the data supporting HER2 targeting in gastric cancers, discuss mechanisms of response and resistance to HER2-directed therapies and summarise the emerging therapies under clinical evaluation that may evolve the way we manage this subset of gastric cancers in the future.
Collapse
|
|
27
|
Immunothérapie dans le traitement du cancer gastrique métastatique. Bull Cancer 2022; 109:1066-1072. [DOI: 10.1016/j.bulcan.2022.07.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 07/04/2022] [Accepted: 07/08/2022] [Indexed: 11/21/2022]
|
|
28
|
Wei J, Lu X, Liu Q, Fu Y, Liu S, Li L, Liu F, Fan X, Yang J, Yang Y, Zhao Y, Guan W, Liu B. Efficacy and Safety of Sintilimab in Combination with Concurrent Chemoradiotherapy for Locally Advanced Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma (SHARED): Study Protocol of a Prospective, Multi-Center, Single-Arm Phase 2 Trial. Cancer Manag Res 2022; 14:2007-2015. [PMID: 35747712 PMCID: PMC9211075 DOI: 10.2147/cmar.s355687] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Accepted: 06/01/2022] [Indexed: 12/23/2022] Open
Abstract
Purpose Concurrent chemoradiotherapy (cCRT) is the mainstay therapy of locally advanced gastric (G) and gastroesophageal junction (GEJ) cancers with a poor prognosis. Programmed cell death receptor-1 (PD-1) inhibitor has been approved and recommended to treat ≥3 line G/GEJ patients. A significant clinical benefit of PD-1 inhibitors in addition to cCRT has been observed in locally advanced lung cancer. Sintilimab, a humanized IgG4 monoclonal antibody with high affinity and specificity for PD-1, has shown promising efficacy with an overall response rate of 85% in combination with chemotherapy in gastric cancer in a phase Ib study (NCT02937116). Patients and Methods SHARED is a prospective, multicentre, single-arm Phase II trial in China, exploring the efficacy of sintilimab in combination with cCRT in locally advanced G/GEJ adenocarcinoma. According to a Simon optimal two-stage clinical design, 34 patients will be enrolled. All the eligible patients will receive one cycle of induction chemotherapy (S-1 plus nab-PTX) combined with sintilimab, followed by cCRT (radiotherapy plus nab-PTX) combined with sintilimab. Prior to the surgery, patients will receive another cycle of chemotherapy (S-1 plus nab-PTX) combined with sintilimab. In the adjuvant setting, all participants will be treated with 3 cycles of chemotherapy (S-1 plus nab-PTX) combined with sintilimab. The primary endpoint is the rate of pathological complete response (pCR). The secondary endpoints include disease-free survival (DFS), major pathological response (MPR), R0 resection rate, surgical AEs, overall survival (OS), event-free survival (EFS), and safety profile. Moreover, the prognostic value of tumor biomarkers and immune biomarkers will be explored. Conclusion SHARED is designed to primally evaluate the efficacy and safety of sintilimab in combination with cCRT in locally advanced G/GEJ cancers and to prospectively validate the prognostic value of tumor biomarkers and immune biomarkers.
Collapse
Affiliation(s)
- Jia Wei
- The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing, 210008, People's Republic of China
| | - Xiaofeng Lu
- Department of General Surgery, Drum Tower Hospital, Nanjing, 210008, People's Republic of China
| | - Qin Liu
- The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing, 210008, People's Republic of China
| | - Yao Fu
- Department of Pathology, Drum Tower Hospital, Nanjing, 210008, People's Republic of China
| | - Song Liu
- Department of Radiology, Drum Tower Hospital, Nanjing, 210008, People's Republic of China
| | - Lin Li
- Department of Pathology, Drum Tower Hospital, Nanjing, 210008, People's Republic of China
| | - Fangcen Liu
- Department of Pathology, Drum Tower Hospital, Nanjing, 210008, People's Republic of China
| | - Xiangshan Fan
- Department of Pathology, Drum Tower Hospital, Nanjing, 210008, People's Republic of China
| | - Ju Yang
- The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing, 210008, People's Republic of China
| | - Yang Yang
- The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing, 210008, People's Republic of China
| | - Yang Zhao
- Department of Biostatistics, Nanjing Medical University, Nanjing, 210029, People's Republic of China
| | - Wenxian Guan
- Department of General Surgery, Drum Tower Hospital, Nanjing, 210008, People's Republic of China
| | - Baorui Liu
- The Comprehensive Cancer Centre of Drum Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing, 210008, People's Republic of China
| |
Collapse
|
|
29
|
Li YF, Wang Y, Zhou J, Wei YC, Lin J, Yin YX, Chen GM, Zhang FY, Chen S, Zhou ZW, Chen YB, Cong Nie R. Surrogate Endpoints for Overall Survival in Immune-Oncology Trials of Advanced Gastro-Esophageal Carcinoma. World J Oncol 2022; 13:126-135. [PMID: 35837321 PMCID: PMC9239497 DOI: 10.14740/wjon1481] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 05/19/2022] [Indexed: 11/22/2022] Open
Abstract
Background We aimed to assess whether the Response Evaluation Criteria in Solid Tumors (RECIST)-based objective response rate (ORR), disease control rate (DCR) and progression-free survival (PFS) could serve as surrogate endpoints for overall survival (OS) in immune-oncology (IO) trials of advanced gastro-esophageal (GE) carcinoma. Methods Randomized controlled trials (RCTs) of IO that reported RECIST-based endpoints and OS in advanced GE carcinoma were screened. Surrogacy of endpoints for OS was assessed based on the correlation between endpoints with OS (arm-level), and between treatment effects on endpoints (trial-level). The correlations were quantified by Pearson correlation coefficient (R). Leave-one-out cross-validation was used to assess the prediction accuracy of surrogate model. Results Seventeen RCTs (9,657 subjects) with 20 comparisons were included. The correlations between DCR and OS were not strong at arm- (R = 0.80) and trial-levels (R = 0.45), but strong correlations between ORR (R = 0.91), PFS (R = 0.89) and OS at arm-level were observed. Treatment effect on ORR and PFS (both R = 0.71) was moderately correlated with treatment effect on OS. Leave-one-out cross-validation approach further validated the surrogacy of PFS. Our analysis showed that 3-month PFS could reliably predict 6-month OS, 6-month PFS could reliably predict 12-month OS, and 12-month PFS could reliably predict 18-month OS. The conservative minimum threshold effect of HRPFS was 0.73. Conclusions PFS may be the appropriate surrogate for OS in IO trials of GE carcinoma. A conservative minimum threshold effect of HRPFS ≤ 0.73 has the potential to predict a significant improvement in OS.
Collapse
Affiliation(s)
- Yuan Fang Li
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
- These authors contributed equally to this study
| | - Yun Wang
- State Key Laboratory of Oncology in South China, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
- Department of Hematologic Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China
- These authors contributed equally to this study
| | - Jie Zhou
- State Key Laboratory of Oncology in South China, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
- Sun Yat-sen University Cancer Center, Guangzhou, China
- These authors contributed equally to this study
| | - Yi Cheng Wei
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
- These authors contributed equally to this study
| | - Jun Lin
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Yi Xin Yin
- State Key Laboratory of Oncology in South China, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
- Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Guo Ming Chen
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Fei Yang Zhang
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Shi Chen
- Department of Gastrointestinal Surgery, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zhi Wei Zhou
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Ying Bo Chen
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Run Cong Nie
- Department of Gastric Surgery, Sun Yat-sen University Cancer Center, Guangzhou, China
- State Key Laboratory of Oncology in South China, Guangzhou, China
- Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| |
Collapse
|
|
30
|
Current Role of Immunotherapy in Gastric, Esophageal and Gastro-Esophageal Junction Cancers—A Report from the Western Canadian Gastrointestinal Cancer Consensus Conference. Curr Oncol 2022; 29:3160-3170. [PMID: 35621647 PMCID: PMC9139288 DOI: 10.3390/curroncol29050257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 04/20/2022] [Accepted: 04/28/2022] [Indexed: 12/24/2022] Open
Abstract
Gastric, esophageal and gastro-esophageal junction cancers are associated with inferior outcomes. For early-stage disease, perioperative chemotherapy or chemoradiation followed by surgery is the standard treatment. For most patients with advanced upper gastrointestinal tract cancers, platinum-based chemotherapy remains a standard treatment. Recently, several randomized clinical trials have demonstrated the benefit of immunotherapy involving checkpoint inhibitors alone or in combination with chemotherapy in patients with gastro-esophageal cancer and have changed the treatment landscape. The Western Canadian Gastrointestinal Cancer Consensus Conference (WCGCCC), involving experts from four Western Canadian provinces, convened virtually on 16 June 2021 and developed the recommendations on the role of immunotherapy in patients with gastro-esophageal cancer.
Collapse
|
|
31
|
Sato Y, Okamoto K, Miyamoto H, Takayama T. Chemotherapy in older adults with gastrointestinal cancer:Current practices and future directions in Japan. THE JOURNAL OF MEDICAL INVESTIGATION 2022; 69:25-30. [PMID: 35466142 DOI: 10.2152/jmi.69.25] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022]
Abstract
Chemotherapy for cancer has significantly improved owing to the increasing number of effective chemotherapeutic agents and supportive care. Recently, the number of older cancer patients has rapidly increased owing to the aging of the global population. However, in most cases, it is difficult to treat those using similar dosages or schedules as that of younger patients because older patients generally have unfavorable factors, such as decreased performance status and physical and cognitive conditions, thus increasing the incidence of complications and side effects. Chemotherapy for gastrointestinal cancers has made significant progress in recent years with the introduction of molecular-targeted agents and immunotherapy. However, clinical trials showed limited evidence regarding the efficacy of chemotherapy in older cancer patients, accounting for half of all patients, making it difficult to develop a well-established treatment strategy. This review aimed to evaluate the current state of chemotherapy for gastrointestinal cancer in older adults. Furthermore, the limitations and future perspectives were discussed. J. Med. Invest. 69 : 25-30, February, 2022.
Collapse
Affiliation(s)
- Yasushi Sato
- Department of Community Medicine for Gastroenterology and Oncology, Tokushima University Graduate School of Medical Science, Tokushima, Japan
| | - Koichi Okamoto
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Medical Science, Tokushima, Japan
| | - Hiroshi Miyamoto
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Medical Science, Tokushima, Japan
| | - Tetsuji Takayama
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Medical Science, Tokushima, Japan
| |
Collapse
|
|
32
|
Booth ME, Smyth EC. Immunotherapy in Gastro-Oesophageal Cancer: Current Practice and the Future of Personalised Therapy. BioDrugs 2022; 36:473-485. [PMID: 35384619 DOI: 10.1007/s40259-022-00527-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/07/2022] [Indexed: 11/02/2022]
Abstract
Initial studies of immune checkpoint inhibitors in biomarker unselected gastro-oesophageal cancer yielded limited improvement in survival. However, emerging data from recent clinical trials suggest immunotherapies may offer a meaningful clinical benefit within selected populations. Gastro-oesophageal cancer is a heterogeneous disease with respect to histopathological and molecular features; hypermutation and the biology of immune checkpoint pathways are key to appropriate selection of populations most likely to benefit from immune checkpoint inhibitors. Programmed death-ligand 1 expression, typically measured using the combined positive score, is an important biomarker in determining which patients may benefit from immunotherapy agents. However, combined positive score thresholds are not standardised across trials and the benefit in programmed death-ligand 1-negative cohorts is uncertain. Data suggest that patients with tumours with microsatellite instability, high tumour mutational burden and Epstein-Barr Virus positivity are more likely to benefit from immunotherapy, which may be of importance within programmed death-ligand 1-negative populations. Here, we describe the current evidence base for the use of checkpoint inhibitors in the treatment of advanced gastro-oesophageal cancer and adjuvant treatment of high-risk oesophageal cancer, as well as the ongoing studies of immunotherapy in the treatment of patients with gastro-oesophageal cancers across an increasing range of clinical settings.
Collapse
Affiliation(s)
| | - Elizabeth C Smyth
- Department of Oncology, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge, UK
| |
Collapse
|
|
33
|
Schlottmann F, Casas MA, Molena D. Evidence-based approach to the treatment of esophagogastric junction tumors. World J Clin Oncol 2022; 13:159-167. [PMID: 35433293 PMCID: PMC8966513 DOI: 10.5306/wjco.v13.i3.159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2021] [Revised: 06/14/2021] [Accepted: 02/15/2022] [Indexed: 02/06/2023] Open
Abstract
The incidence of esophagogastric junction (EGJ) adenocarcinoma is increasing in developed nations due to the rising prevalence of obesity and gastroesophageal reflux disease. Due to the peculiar location in a histological transition zone between the esophagus and the stomach, the management of EGJ tumors is controversial. Two main surgical approaches exist: total gastrectomy with distal esophagectomy or esophagectomy by either transhiatal or transthoracic approach. These operations differ significantly in the extent of lymphadenectomy. In addition, patients with locally advanced disease can receive either preoperative chemoradiation or perioperative chemotherapy. This evidence-based review analyzes current evidence regarding the management of EGJ tumors in order to help defining the best surgical and systemic treatment of these patients.
Collapse
Affiliation(s)
- Francisco Schlottmann
- Department of Surgery, Hospital Alemán of Buenos Aires, Buenos Aires C1118AAT, Argentina
| | - María A Casas
- Department of Surgery, Hospital Alemán of Buenos Aires, Buenos Aires C1118AAT, Argentina
| | - Daniela Molena
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, United States
| |
Collapse
|
|
34
|
Ooki A, Yamaguchi K. The dawn of precision medicine in diffuse-type gastric cancer. Ther Adv Med Oncol 2022; 14:17588359221083049. [PMID: 35281349 PMCID: PMC8908406 DOI: 10.1177/17588359221083049] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Accepted: 01/31/2022] [Indexed: 12/24/2022] Open
Abstract
Gastric cancer (GC) is one of the most common malignancies worldwide. The histology- and morphology-based Lauren classification of GC has been widely used for over 50 years in clinical practice. The Lauren classification divides GC into intestinal and diffuse types, which have distinct etiology, molecular profiles, and clinicopathological features. Diffuse-type GC (DGC) accounts for approximately 30% of GCs. Tumor cells lack adhesion and infiltrate the stroma as single cells or small subgroups, leading to easy dissemination in the abdominal cavity. Clinically, DGC has aggressive traits with a high risk of recurrence and metastasis, which results in unfavorable prognosis. Although systemic chemotherapy is the main therapeutic approach for recurrent or metastatic GC patients, clinical benefits are limited for patients with DGC. Therefore, it is urgent to develop effective therapeutic strategies for DGC patients. Considerable research studies have characterized the molecular and genomic landscape of DGC, of which tight junction protein claudin-18 isoform 2 (CLDN18.2) and fibroblast growing factors receptor-2 isoform IIIb (FGFR2-IIIb) are the most attractive targets because of their close association with DGC. Recently, the impressive results of two phase II FAST and FIGHT trials demonstrate proof-of-concept, suggesting that anti-CLDN18.2 antibody (zolbetuximab) and FGFR2-IIIb antibody (bemarituzumab) are promising approaches for patients with CLDN18.2-positive and FGFR2-IIIb-positive GC, respectively. In this review, we summarize the clinicopathological features and molecular profiles of DGC and highlight a potential therapeutic target based on the findings of pivotal clinical trials.
Collapse
Affiliation(s)
- Akira Ooki
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan
| | - Kensei Yamaguchi
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| |
Collapse
|
|
35
|
Recent insights into the use of immune checkpoint inhibitors in gastric cancer. Porto Biomed J 2022; 7:e162. [PMID: 35146175 PMCID: PMC8824404 DOI: 10.1097/j.pbj.0000000000000162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 06/08/2021] [Accepted: 06/09/2021] [Indexed: 11/26/2022] Open
Abstract
Gastric cancer (GC) is the fifth most incident and the fourth deadliest cancer worldwide. GC is a heterogeneous disease from the histological and molecular standpoints. This malignancy is mostly diagnosed at advanced stages of the disease, where the available therapeutic interventions are not effective. The emergence of immunotherapy has transformed the landscape of cancer treatment, including GC, and currently immune checkpoint inhibitors have been approved for the treatment of patients with recurrent/metastatic GC. This review summarizes the main clinical trials evaluating the use of immune checkpoint inhibitors in GC. It also highlights the potential of biomarkers for patient selection for GC immune checkpoint inhibition therapy, including programmed cell death ligand 1 expression and tumor mutational burden, and characteristics of the GC molecular classification, such as microsatellite instability status and Epstein-Barr virus infection, as predictors of response to blockade of the programmed cell death 1/programmed cell death ligand 1 axis.
Collapse
|
|
36
|
Bhargava P, Shrikhande SV. First-line immunotherapy: Hype rather than near reality in gastric cancer. THE NATIONAL MEDICAL JOURNAL OF INDIA 2022; 35:98-99. [PMID: 36461855 DOI: 10.25259/nmji_645_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/17/2023]
Affiliation(s)
- Prabhat Bhargava
- Department of Medical Oncology, Homi Bhabha National Institute, Tata Memorial Centre Parel, Mumbai, Maharashtra, India
| | - Shailesh V Shrikhande
- Department of GI and HPB Surgical Oncology, Homi Bhabha National Institute, Tata Memorial Centre Parel, Mumbai, Maharashtra, India
| |
Collapse
|
|
37
|
Costa G, Younes H, Kourie HR, Kattan J. The rapidly evolving landscape of advanced gastric cancer therapy. Future Oncol 2022; 18:1413-1416. [PMID: 35129395 DOI: 10.2217/fon-2021-1499] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Affiliation(s)
- Georges Costa
- Department of Hematology-Oncology, Faculty of Medicine, Saint Joseph University, Beirut, 1100, Lebanon
| | - Hadi Younes
- Department of Hematology-Oncology, Faculty of Medicine, Saint Joseph University, Beirut, 1100, Lebanon
| | - Hampig Raphael Kourie
- Department of Hematology-Oncology, Faculty of Medicine, Saint Joseph University, Beirut, 1100, Lebanon
| | - Joseph Kattan
- Department of Hematology-Oncology, Faculty of Medicine, Saint Joseph University, Beirut, 1100, Lebanon
| |
Collapse
|
|
38
|
Moy RH, Greally M, Chou JF, Li J, Desai AM, Chalasani SB, Won E, Kelsen DP, Ilson DH, Janjigian YY, Capanu M, Ku GY. Phase I/Ib study of crenolanib with ramucirumab and paclitaxel as second-line therapy for advanced esophagogastric adenocarcinoma. Cancer Chemother Pharmacol 2022; 89:255-265. [PMID: 35066693 DOI: 10.1007/s00280-021-04384-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Accepted: 12/10/2021] [Indexed: 01/25/2023]
Abstract
PURPOSE Paclitaxel plus ramucirumab is a standard second-line regimen for patients with advanced gastric adenocarcinoma, but clinical benefit remains modest. One potential resistance mechanism to VEGFR2 inhibition is activation of the PDGF/PDGFR pathway, which can be blocked by the selective inhibitor crenolanib. Therefore, we performed a phase I/Ib study of crenolanib in combination with paclitaxel/ramucirumab. METHODS Patients with metastatic esophagogastric adenocarcinoma refractory to first-line therapy received escalating doses of crenolanib [60 mg twice daily (BID) to 100 mg three times daily (TID)] in combination with paclitaxel 80 mg/m2 intravenously on days 1, 8 and 15 and ramucirumab 8 mg/kg intravenously on days 1 and 15 of a 28-day cycle. The primary objective was to determine the maximally tolerated dose (MTD) of crenolanib. Additional patients were enrolled in the dose expansion cohort to assess 6-month progression-free survival (PFS) at the MTD. RESULTS We enrolled 19 patients in the dose escalation phase and 8 patients in the dose expansion phase at the MTD of crenolanib 100 mg BID. Common grade 3/4 treatment-emergent adverse events included leukopenia (19%), anemia (11%) and neutropenia (11%). In the 14 patients treated at the MTD, 6-month PFS was 43% [95% confidence interval (CI) 23-78%] and the objective response rate (ORR) was 42% (95% CI 15-72%). The trial was terminated early due to withdrawal of crenolanib by the sponsor. CONCLUSIONS The addition of crenolanib to paclitaxel/ramucirumab is safe and well-tolerated at a dose level up to 100 mg BID. CLINICAL TRIAL REGISTRATION NCT03193918. June 19, 2017.
Collapse
Affiliation(s)
- Ryan H Moy
- Department of Medicine, Memorial Sloan Kettering Cancer Center, 300 E. 66th St., Room 1035, New York, NY, 10065, USA
- Division of Hematology and Oncology, Department of Medicine, Columbia University Medical Center, New York, NY, USA
| | - Megan Greally
- Department of Medicine, Memorial Sloan Kettering Cancer Center, 300 E. 66th St., Room 1035, New York, NY, 10065, USA
| | - Joanne F Chou
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jia Li
- Department of Medicine, Memorial Sloan Kettering Cancer Center, 300 E. 66th St., Room 1035, New York, NY, 10065, USA
| | - Avni M Desai
- Department of Medicine, Memorial Sloan Kettering Cancer Center, 300 E. 66th St., Room 1035, New York, NY, 10065, USA
| | - Sree B Chalasani
- Department of Medicine, Memorial Sloan Kettering Cancer Center, 300 E. 66th St., Room 1035, New York, NY, 10065, USA
| | - Elizabeth Won
- Department of Medicine, Memorial Sloan Kettering Cancer Center, 300 E. 66th St., Room 1035, New York, NY, 10065, USA
| | - David P Kelsen
- Department of Medicine, Memorial Sloan Kettering Cancer Center, 300 E. 66th St., Room 1035, New York, NY, 10065, USA
| | - David H Ilson
- Department of Medicine, Memorial Sloan Kettering Cancer Center, 300 E. 66th St., Room 1035, New York, NY, 10065, USA
| | - Yelena Y Janjigian
- Department of Medicine, Memorial Sloan Kettering Cancer Center, 300 E. 66th St., Room 1035, New York, NY, 10065, USA
| | - Marinela Capanu
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Geoffrey Y Ku
- Department of Medicine, Memorial Sloan Kettering Cancer Center, 300 E. 66th St., Room 1035, New York, NY, 10065, USA.
| |
Collapse
|
|
39
|
Neutrophil-to-Lymphocyte Ratio (NLR) Predicts PD-1 Inhibitor Survival in Patients with Metastatic Gastric Cancer. J Immunol Res 2022; 2021:2549295. [PMID: 34993252 PMCID: PMC8727102 DOI: 10.1155/2021/2549295] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Accepted: 11/24/2021] [Indexed: 12/14/2022] Open
Abstract
Background and Aims Biomarkers for systemic inflammation have been introduced into clinical practice for risk-rating in cancer patients' treatment. This study is aimed at confirming the prognostic role of the neutrophil-to-lymphocyte ratio (NLR) as an effective biomarker for patients with metastatic gastric cancer (MGC) receiving anti-PD-1 agents. Method Patients with MGC who received anti-PD-1 treatment at the Chinese PLA General Hospital between January 2016 and November 2020 were reviewed. The study analyzed the association of NLR and overall survival (OS) or progression-free survival (PFS) and antitumor response rate with PD-1 inhibitors. Results 137 patients were included in the final analysis. The area under the curve value of NLR for 6-month OS was 0.71. The best cut-off value for NLR was 3.23. NLR < 3.23 was associated with longer OS (HR = 0.38, 95% CI, 0.26-0.57, p < 0.001) and PFS (HR = 0.42, 95% CI, 0.29-0.62, p < 0.001) in patients with MGC. No significant difference was observed in the objective response rate (ORR) (35.8% vs. 28.6%, p = 0.377) and disease control rate (DCR) (86.4% vs. 78.6%, p = 0.229) in the NLR < 3.23 group and in the NLR ≥ 3.23 group, respectively. Univariate analysis and multivariate analysis found that NLR was an independent prognosis biomarker for PFS and OS. Conclusions Pretreatment elevated NLR was significantly associated with inferior PFS and OS in patients with MGC who received anti-PD-1 inhibitors. Clinicians need to consider patients with elevated NLR for decisions on immunotherapy strategy.
Collapse
|
|
40
|
Immunotherapy in Gastrointestinal Malignancies. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1342:259-272. [PMID: 34972968 DOI: 10.1007/978-3-030-79308-1_8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Gastrointestinal (GI) cancers represent a heterogeneous group of malignancies, each with a unique tumor biology that in turn affects response to treatment and subsequent prognosis. The interplay between tumor cells and the local immune microenvironment also varies within each GI malignancy and can portend prognosis and response to therapy. Treatment with immune checkpoint inhibitors has changed the treatment landscape of various solid tumors including (but not limited to) renal cell carcinoma, melanoma, and lung cancer. Advances in the understanding between the interplay between the immune system and tumors cells have led to the integration of immunotherapy as standard of care in various GI malignancies. For example, immunotherapy is now a mainstay of treatment for tumors harboring defects in DNA mismatch repair proteins and tumors harboring a high mutational load, regardless of primary site of origin. Data from recent clinical trials have led to the integration of immunotherapy as standard of care for a subset of gastroesophageal cancers and hepatocellular carcinoma. Here, we outline the current landscape of immunotherapy in GI malignancies and highlight ongoing clinical trials that will likely help to further our understanding of how and when to integrate immunotherapy into the treatment of various GI malignancies.
Collapse
|
|
41
|
Mei Y, Shi M, Zhu Z, Yuan H, Yan C, Li C, Feng T, Yan M, Zhang J, Zhu Z. Addition of sintilimab to nanoparticle albumin-bound paclitaxel and S-1 as adjuvant therapy in stage IIIC gastric cancer. Future Oncol 2022; 18:139-148. [PMID: 34877867 DOI: 10.2217/fon-2021-1020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Accepted: 10/22/2021] [Indexed: 11/21/2022] Open
Abstract
The prognosis of stage III gastric cancer (GC) is not satisfying and the specific chemotherapy regimens for GC of stage IIIC based on the 8th edition of the UICC/AJCC TNM staging system are still inconclusive. Peritoneal recurrence is the common and severe relapse pattern. Nanoparticle albumin-bound paclitaxel (Nab-PTX) is safer and more effective than PTX in the peritoneal metastasis. Clinical trial has demonstrated the safety and efficacy of sintilimab in GC. A combination of Nab-PTX, S-1 and sintilimab could be a promising triplet regimen as adjuvant therapy for GC. The aim of this article is to describe the design of this prospective Dragon-VII trial, conducted to evaluate the safety and efficacy of the combination of Nab-PTX, S-1 and sintilimab. Clinical trial registration: NCT04781413.
Collapse
MESH Headings
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Albumins/administration & dosage
- Albumins/adverse effects
- Antibodies, Monoclonal, Humanized/administration & dosage
- Antibodies, Monoclonal, Humanized/adverse effects
- Antineoplastic Combined Chemotherapy Protocols/administration & dosage
- Antineoplastic Combined Chemotherapy Protocols/adverse effects
- Chemotherapy, Adjuvant/adverse effects
- Chemotherapy, Adjuvant/methods
- Clinical Trials, Phase I as Topic
- Clinical Trials, Phase II as Topic
- Disease-Free Survival
- Drug Administration Schedule
- Drug Combinations
- Feasibility Studies
- Female
- Gastrectomy
- Humans
- Incidence
- Male
- Middle Aged
- Neoplasm Recurrence, Local/epidemiology
- Neoplasm Recurrence, Local/prevention & control
- Neoplasm Staging
- Oxonic Acid/administration & dosage
- Oxonic Acid/adverse effects
- Paclitaxel/administration & dosage
- Paclitaxel/adverse effects
- Peritoneal Neoplasms/diagnosis
- Peritoneal Neoplasms/epidemiology
- Peritoneal Neoplasms/prevention & control
- Prospective Studies
- Stomach Neoplasms/diagnosis
- Stomach Neoplasms/mortality
- Stomach Neoplasms/pathology
- Stomach Neoplasms/therapy
- Tegafur/administration & dosage
- Tegafur/adverse effects
- Young Adult
Collapse
Affiliation(s)
- Yu Mei
- Department of General Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Min Shi
- Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Zhenglun Zhu
- Department of General Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Hong Yuan
- Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Chao Yan
- Department of General Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Chen Li
- Department of General Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Tienan Feng
- Clinical Research Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Min Yan
- Department of General Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Jun Zhang
- Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| | - Zhenggang Zhu
- Department of General Surgery, Shanghai Key Laboratory of Gastric Neoplasms, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
| |
Collapse
|
|
42
|
Baxter MA, Marinho J, Soto-Perez-de-Celis E, Rodriquenz MG, Arora SP, Lok WCW, Shih YY, Liposits G, O'Hanlon S, Petty RD. Gastroesophageal adenocarcinoma in older adults: A comprehensive narrative review of management by the Young International Society of Geriatric Oncology. J Geriatr Oncol 2022; 13:7-19. [PMID: 34548259 DOI: 10.1016/j.jgo.2021.09.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 08/26/2021] [Accepted: 09/07/2021] [Indexed: 12/24/2022]
Abstract
Gastroesophageal adenocarcinoma is a disease of older adults with very poor survival rates. Its incidence has risen dramatically across the world in recent decades. Current treatment approaches for older adults are based largely on extrapolated evidence from clinical trials conducted in younger and fitter participants than those more commonly encountered in clinical practice. Understanding how to apply available evidence to our patients in the clinic setting is essential given the high morbidity of both curative and palliative treatment. This review aims to use available data to inform the management of an older adult with gastroesophageal adenocarcinoma.
Collapse
Affiliation(s)
- Mark A Baxter
- Division of Molecular and Clinical Medicine, University of Dundee, Dundee, UK; Tayside Cancer Centre, Ninewells Hospital, Dundee, UK.
| | - Joana Marinho
- Department of Medical Oncology, Centro Hospitalar Vila Nova de Gaia/Espinho, Vila Nova de Gaia, Portugal; Associação de Investigação de Cuidados de Suporte em Oncologia (AICSO), Espinho, Portugal
| | - Enrique Soto-Perez-de-Celis
- Department of Geriatrics, Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Mexico City, Mexico
| | - Maria Grazia Rodriquenz
- Oncology Unit, Foundation IRCCS, Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Sukeshi Patel Arora
- Mays Cancer Center, University of Texas Health San Antonio, Leader in Gastrointestinal Malignancies, 7979 Wurzbach Rd, 78229 San Antonio, TX, USA
| | - Wendy Chan Wing Lok
- Department of Clinical Oncology, LKS Faculty of Medicine, University of Hong Kong, China
| | - Yung-Yu Shih
- Department of Hematology and Oncology, Kaiser Franz Josef Hospital-Clinic Favoriten, Vienna, Austria
| | - Gabor Liposits
- Department of Oncology, Odense University Hospital, Odense, Denmark; Department of Clinical Research, University of Southern Denmark, Odense, Denmark; Academy of Geriatric Cancer Research (AgeCare), Odense, Denmark
| | - Shane O'Hanlon
- Department of Geriatric Medicine, St Vincent's University Hospital, Dublin, Ireland; University College, Dublin, Ireland
| | - Russell D Petty
- Division of Molecular and Clinical Medicine, University of Dundee, Dundee, UK; Tayside Cancer Centre, Ninewells Hospital, Dundee, UK
| |
Collapse
|
|
43
|
The KEYNOTE-811 trial of dual PD-1 and HER2 blockade in HER2-positive gastric cancer. Nature 2021; 600:727-730. [PMID: 34912120 DOI: 10.1038/s41586-021-04161-3] [Citation(s) in RCA: 466] [Impact Index Per Article: 116.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 09/30/2021] [Indexed: 12/13/2022]
Abstract
Human epidermal growth factor receptor 2 (HER2, also known as ERBB2) amplification or overexpression occurs in approximately 20% of advanced gastric or gastro-oesophageal junction adenocarcinomas1-3. More than a decade ago, combination therapy with the anti-HER2 antibody trastuzumab and chemotherapy became the standard first-line treatment for patients with these types of tumours4. Although adding the anti-programmed death 1 (PD-1) antibody pembrolizumab to chemotherapy does not significantly improve efficacy in advanced HER2-negative gastric cancer5, there are preclinical6-19 and clinical20,21 rationales for adding pembrolizumab in HER2-positive disease. Here we describe results of the protocol-specified first interim analysis of the randomized, double-blind, placebo-controlled phase III KEYNOTE-811 study of pembrolizumab plus trastuzumab and chemotherapy for unresectable or metastatic, HER2-positive gastric or gastro-oesophageal junction adenocarcinoma22 ( https://clinicaltrials.gov , NCT03615326). We show that adding pembrolizumab to trastuzumab and chemotherapy markedly reduces tumour size, induces complete responses in some participants, and significantly improves objective response rate.
Collapse
|
|
44
|
Chung HC, Kang YK, Chen Z, Bai Y, Wan Ishak WZ, Shim BY, Park YL, Koo DH, Lu J, Xu J, Chon HJ, Bai LY, Zeng S, Yuan Y, Chen YY, Gu K, Zhong WY, Kuang S, Shih CS, Qin SK. Pembrolizumab versus paclitaxel for previously treated advanced gastric or gastroesophageal junction cancer (KEYNOTE-063): A randomized, open-label, phase 3 trial in Asian patients. Cancer 2021; 128:995-1003. [PMID: 34878659 PMCID: PMC9299889 DOI: 10.1002/cncr.34019] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Revised: 08/23/2021] [Accepted: 08/24/2021] [Indexed: 01/05/2023]
Abstract
Background KEYNOTE‐063 (NCT03019588) investigated pembrolizumab versus paclitaxel as second‐line therapy in Asian patients with advanced programmed death ligand 1 (PD‐L1)–positive (combined positive score ≥1) gastric/gastroesophageal junction (GEJ) cancer. Methods This randomized, open‐label, phase 3 study was conducted at 36 medical centers in China (mainland), Malaysia, South Korea, and Taiwan. Patients were randomly assigned 1:1 to 200 mg of pembrolizumab intravenously every 3 weeks for ≤2 years or 80 mg/m2 of paclitaxel intravenously every week. Primary end points were overall survival (OS) and progression‐free survival (PFS). Secondary end points were objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 and safety. Results Between February 16, 2017, and March 12, 2018, 94 patients were randomly assigned (47 pembrolizumab/47 paclitaxel) after screening; enrollment was stopped on March 12, 2018, based on the results of the global KEYNOTE‐061 study, and patients were followed until the last patient's last visit. Median OS was 8 months (95% confidence interval [CI], 4‐10 months) with pembrolizumab versus 8 months (95% CI, 5‐11 months) with paclitaxel (hazard ratio [HR], 0.99; 95% CI, 0.63‐1.54). Median PFS was 2 months (95% CI, 1‐3 months) with pembrolizumab versus 4 months (95% CI, 3‐6 months) with paclitaxel (HR, 1.62; 95% CI, 1.04‐2.52). ORR was 13% for pembrolizumab versus 19% for paclitaxel. Any‐grade treatment‐related adverse events occurred in 28 pembrolizumab‐treated patients (60%) and 42 paclitaxel‐treated patients (96%); grades 3 to 5 events occurred in 5 patients (11%) and 28 patients (64%), respectively. Conclusions Definitive conclusions about the efficacy of second‐line pembrolizumab in Asian patients with advanced PD‐L1–positive gastric/GEJ cancer are limited because of insufficient power, but pembrolizumab was well tolerated in this patient population. Efficacy followed a trend similar to that observed in the phase 3 KEYNOTE‐061 trial. In this small sample of Asian patients with advanced PD‐L1–positive (combined positive score [CPS] ≥1) gastric/gastroesophageal junction (GEJ) cancer enrolled in the randomized, open‐label, phase 3 KEYNOTE‐063 study, definitive conclusions on clinical outcomes are limited; however, second‐line pembrolizumab monotherapy seems to be well tolerated in this patient population. These findings are consistent with those of the larger global KEYNOTE‐061 study in patients with CPS ≥1 gastric/GEJ cancer.
Collapse
Affiliation(s)
- Hyun Cheol Chung
- Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea
| | - Yoon-Koo Kang
- Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | | | - Yuxian Bai
- Harbin Medical University Cancer Hospital, Harbin, China
| | | | - Byoung Yong Shim
- St. Vincent's Hospital, The Catholic University of Korea, Gyeonggi-Do, South Korea
| | | | - Dong-Hoe Koo
- Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Jianwei Lu
- Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
| | - Jianming Xu
- The People's Liberation Army General Hospital, Beijing, China
| | | | - Li-Yuan Bai
- China Medical University Hospital and China Medical University, Taichung, Taiwan
| | - Shan Zeng
- Xiangya Hospital, Central South University, Changsha, China
| | - Ying Yuan
- Department of Medical Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Yen-Yang Chen
- Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
| | - Kangsheng Gu
- Hospital of Anhui Medical University, Hefei, China
| | | | | | | | - Shu-Kui Qin
- People's Liberation Army Cancer Centre of Nanjing Bayi Hospital, Nanjing, China
| |
Collapse
|
|
45
|
Kamposioras K, Ntellas P, Nikolaou M, Germetaki T, Gazouli I, Dadouli K, Zarkavelis G, Amylidi AL, Tolia M, Mauri D. Immunotherapy Efficacy in the Initial Lines of Treatment in Advanced Upper Gastrointestinal Malignancies: A Systematic Review of the Literature. JNCI Cancer Spectr 2021; 5:pkab088. [PMID: 34926989 PMCID: PMC8677514 DOI: 10.1093/jncics/pkab088] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 05/11/2021] [Accepted: 10/07/2021] [Indexed: 12/30/2022] Open
Abstract
Background The therapeutic role of immune checkpoint inhibitors (ICIs) has represented the cutting edge of clinical research in upper gastrointestinal (GI) malignancies, with these agents now included in the armamentarium of treatment options for advanced gastric and esophageal cancers. Methods We performed a systematic literature review and pooled analysis to map out the currently available robust clinical evidence for the use of ICIs in upper GI cancers. Immunotherapy (IO), either as monotherapy or in combination with chemotherapy, and its role in first-line, maintenance, and second-line settings, as well as in specific clinical and biological subgroups, were critically appraised. All statistical tests were 2-sided. Results ICIs, in combination with chemotherapy, have provided statistically significant overall survival benefit in the first-line setting in gastric and gastro-esophageal adenocarcinomas (hazard ratio [HR] = 0.83, 95% confidence interval [CI] = 0.76 to 0.90, P < .001; based on 4 studies) and esophageal squamous cell carcinoma (HR = 0.72, 95% CI = 0.64 to 0.81, P < .001; based on 3 studies), albeit with heterogeneous efficacy according to biomarker expression. Patients with esophageal squamous cell carcinoma, and in particular high programmed cell death ligand-1 expression, derive survival benefit when treated with IO in the second-line setting (HR = 0.74, 95% CI = 0.68 to 0.82, P < .001; for any level of programmed cell death ligand-1 expression). Clinical trials interrogating the combination of IO with chemotherapy in second-line treatment should be seriously considered in upper GI adenocarcinomas. The role of maintenance IO after initial disease control is still unclear and cannot be recommended. Impressive response rates and survival benefit from IO have been reported in patients with microsatellite instability-high tumors (HR = 0.33, 95% CI = 0.19 to 0.57, P < .001), and this warrants further prospective biomarker-driven studies. Conclusions IO is changing the treatment landscape in upper GI malignancies. The rapidly developing evidence in the field needs to be critically appraised while further validation of the existing information from ongoing trials is awaited.
Collapse
Affiliation(s)
| | - Panagiotis Ntellas
- Department of Medical Oncology, University Hospital of Ioannina, Ioannina, Greece
| | - Michail Nikolaou
- Department of Medical Oncology, Agios Savvas Anticancer Hospital, Athens, Greece
| | - Theodora Germetaki
- Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
| | - Ioanna Gazouli
- Department of Medical Oncology, University Hospital of Ioannina, Ioannina, Greece
| | - Katerina Dadouli
- Laboratory of Hygiene and Epidemiology, Faculty of Medicine, University of Thessaly, Larissa, Greece
| | - George Zarkavelis
- Department of Medical Oncology, University Hospital of Ioannina, Ioannina, Greece
| | - Anna-Lea Amylidi
- Department of Medical Oncology, University Hospital of Ioannina, Ioannina, Greece
| | - Maria Tolia
- Department of Radiotherapy, School of Medicine, University of Crete, Heraklion, Greece
| | - Davide Mauri
- Department of Medical Oncology, University Hospital of Ioannina, Ioannina, Greece
| |
Collapse
|
|
46
|
Ooki A, Yamaguchi K. The beginning of the era of precision medicine for gastric cancer with fibroblast growth factor receptor 2 aberration. Gastric Cancer 2021; 24:1169-1183. [PMID: 34398359 DOI: 10.1007/s10120-021-01235-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Accepted: 08/11/2021] [Indexed: 02/07/2023]
Abstract
Despite recent advances in the systemic treatment of metastatic gastric cancer (GC), prognostic outcomes remain poor. Considerable research effort has been invested in characterizing the genomic landscape of GC and identifying potential therapeutic targets. FGFR2 is one of the most attractive targets because aberrations in this gene are frequently associated with GC, particularly the diffuse type in Lauren's classification, which confers an unfavorable prognosis. Based on the preclinical data, the FGFR2 signaling pathway plays a key role in the development and progression of GC, and several FGFR inhibitors have been clinically assessed. However, the lack of robust treatment efficacy has hampered precision medicine for patients with FGFR2-aberrant GC. Recently, the clinical benefits of the FGFR2-IIIb-selective monoclonal antibody bemarituzumab for FGFR2b-positive GC patients were shown in a randomized phase II FIGHT trial of bemarituzumab combined with the first-line chemotherapy. This trial demonstrates proof of concept, suggesting that FGFR2 is a relevant therapeutic target for patients with FGFR2b-positive GC and that bemarituzumab brings new hope for diffuse-type GC patients. In this review, we summarize the oncogenic roles of FGFR2 signaling and highlight the most recent advances in FGFR inhibitors based on the findings of pivotal clinical trials for patients with FGFR2-aberrant GC. Thus, the era of precision medicine for patients with FGFR2-aberrant GC will be opened.
Collapse
Affiliation(s)
- Akira Ooki
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan.
| | - Kensei Yamaguchi
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan
| |
Collapse
|
|
47
|
de la Fouchardiere C, Decoster L, Samalin E, Terret C, Kenis C, Droz JP, Coutzac C, Smyth E. Advanced oesophago-gastric adenocarcinoma in older patients in the era of immunotherapy. A review of the literature. Cancer Treat Rev 2021; 100:102289. [PMID: 34583303 DOI: 10.1016/j.ctrv.2021.102289] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 09/05/2021] [Accepted: 09/06/2021] [Indexed: 12/15/2022]
Abstract
Gastric (G) and gastro-esophageal junction (GEJ) adenocarcinomas are of the most common and deadly cancers worldwide and affect mainly patients over 70 years at diagnosis. Older age has been associated in gastric cancers with distal tumour location, well-differentiated adenocarcinoma and microsatellite instability and is not identified itself as an independent prognostic factor. As immune checkpoint inhibitors recently changed the landmark of advanced G and GEJ adenocarcinomas treatment, we decided to perform a literature review to define the evidence-level of clinical data in older patients. This work underlined the lasting low -inclusion rate of older patients and -implementation rate of frailty screening tools in clinical trials in G/GEJ carcinomas. In the first-line metastatic setting, two prospective randomized phase III studies have specifically assessed the efficacy of chemotherapy in older patients with HER2-negative gastric cancers, demonstrating the feasibility of reduced dose oxaliplatin-based chemotherapy regimen in this population. Only few data are available in HER2-positive tumors, or in the second-line setting. Furthermore, no specific trial with immune checkpoint inhibitors was performed in older frail patients whereas their benefit/adverse events ratio make them attractive candidates in this patient's population. We conclude that older fit patients can be treated in the same way as younger ones and included in clinical trials. Improving the outcome of older frail patients should be the oncology community next focus by implementing targeted interventions before initiating cancer therapy and designing specific clinical trials. Frailty screening tools and geriatric data collection have to be implemented in routine-practice and clinical trials.
Collapse
Affiliation(s)
| | - L Decoster
- Department of Medical Oncology, Universitair Ziekenhuis Brussel (UZ Brussel), Vrije Universiteit Brussel (VUB), Brussels, Belgium.
| | - E Samalin
- Medical Oncology Department, Institut du Cancer de Montpellier (ICM), Univ. Montpellier, Montpellier, France.
| | - C Terret
- Medical Oncology Department, Centre Léon Bérard, 28 rue Laennec, Lyon, France
| | - C Kenis
- Department of General Medical Oncology and Geriatric Medicine, University Hospitals Leuven, Leuven, Belgium; Department of Public Health and Primary Care, Academic Centre for Nursing and Midwifery, KU Leuven - University of Leuven, Leuven, Belgium.
| | - J P Droz
- Medical Oncology, Claude-Bernard Lyon1 University, Lyon, France.
| | - C Coutzac
- Medical Oncology Department, Centre Léon Bérard, 28 rue Laennec, Lyon, France.
| | - E Smyth
- Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom.
| |
Collapse
|
|
48
|
Molecular Targets for Gastric Cancer Treatment and Future Perspectives from a Clinical and Translational Point of View. Cancers (Basel) 2021; 13:cancers13205216. [PMID: 34680363 PMCID: PMC8533881 DOI: 10.3390/cancers13205216] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 10/05/2021] [Accepted: 10/13/2021] [Indexed: 12/11/2022] Open
Abstract
Gastric cancer is a leading cause of cancer death worldwide. Systemic treatment comprising chemotherapy and targeted therapy is the standard of care in advanced/metastatic gastric cancer. Comprehensive molecular characterization of gastric adenocarcinomas by the TCGA Consortium and ACRG has resulted in the definition of distinct molecular subtypes. These efforts have in parallel built a basis for the development of novel molecularly stratified treatment approaches. Based on this molecular characterization, an increasing number of specific genomic alterations can potentially serve as treatment targets. Consequently, the development of promising compounds is ongoing. In this review, key molecular alterations in gastric and gastroesophageal junction cancers will be addressed. Finally, the current status of the translation of targeted therapy towards clinical applications will be reviewed.
Collapse
|
|
49
|
Larroquette M, Domblides C, Lefort F, Lasserre M, Quivy A, Sionneau B, Bertolaso P, Gross-Goupil M, Ravaud A, Daste A. Combining immune checkpoint inhibitors with chemotherapy in advanced solid tumours: A review. Eur J Cancer 2021; 158:47-62. [PMID: 34655837 DOI: 10.1016/j.ejca.2021.09.013] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Accepted: 09/11/2021] [Indexed: 12/30/2022]
Abstract
The use of immune checkpoint inhibitors (ICIs), especially anti-programmed cell death 1 (PD1) and anti-programmed cell death ligand 1 (PD-L1), has changed practices in oncology, becoming a new standard of care in first or subsequent lines for several cancer subtypes. Recent data have highlighted the ability of standard chemotherapy to enhance immunogenicity and/or to break immunoresistance of the tumour and its microenvironment, leading to a rationale for the use of ICIs in combination with the standard chemotherapy regimen to improve efficacy of cancer treatment. Here, we propose to review randomised clinical trials evaluating concomitant administration of ICIs and chemotherapy, to assess clinical efficacy and safety profiles in advanced solid tumours. Association of these two modes of action on treatments has shown improved overall survival and better objective response rates than standard chemotherapy, especially in first-line treatment of non-small cell lung cancer (NSCLC) and for PD1/PD-L1 enriched tumours, highlighting a potential synergistic effect of this treatment combination in certain tumour types. However, improved survival results with the use of anti-PD-L1 avelumab as a maintenance schedule for bladder cancer raises the question of the most appropriate approach between sequential and concomitant administration of chemoimmunotherapy. To date, no trials have compared in a head-to-head protocol the administration of concomitant chemoimmunotherapy with chemotherapy, used for tumour debulking, followed by administration of ICIs. Regarding the tolerance profile, no new safety signals were found with the combination tested to date. Interestingly, recent results have shown an improved Progression Free survival 2 (PFS2) (defined as the progression after the next line of therapy) in head-and-neck cancers or NSCLC after a first-line pembrolizumab-chemotherapy combination, suggesting a potential long-lasting effect of ICIs when used in combination in the first-line setting.
Collapse
Affiliation(s)
- Mathieu Larroquette
- Department of Medical Oncology, Hôpital Saint-André, Bordeaux University Hospital-CHU, Bordeaux, France; Bordeaux University, Bordeaux, France
| | - Charlotte Domblides
- Department of Medical Oncology, Hôpital Saint-André, Bordeaux University Hospital-CHU, Bordeaux, France; Bordeaux University, Bordeaux, France
| | - Félix Lefort
- Department of Medical Oncology, Hôpital Saint-André, Bordeaux University Hospital-CHU, Bordeaux, France
| | - Matthieu Lasserre
- Department of Medical Oncology, Hôpital Saint-André, Bordeaux University Hospital-CHU, Bordeaux, France; Bordeaux University, Bordeaux, France
| | - Amandine Quivy
- Department of Medical Oncology, Hôpital Saint-André, Bordeaux University Hospital-CHU, Bordeaux, France
| | - Baptiste Sionneau
- Department of Medical Oncology, Hôpital Saint-André, Bordeaux University Hospital-CHU, Bordeaux, France
| | - Pauline Bertolaso
- Department of Medical Oncology, Hôpital Saint-André, Bordeaux University Hospital-CHU, Bordeaux, France
| | - Marine Gross-Goupil
- Department of Medical Oncology, Hôpital Saint-André, Bordeaux University Hospital-CHU, Bordeaux, France
| | - Alain Ravaud
- Department of Medical Oncology, Hôpital Saint-André, Bordeaux University Hospital-CHU, Bordeaux, France
| | - Amaury Daste
- Department of Medical Oncology, Hôpital Saint-André, Bordeaux University Hospital-CHU, Bordeaux, France.
| |
Collapse
|
|
50
|
Catenacci DV, Chao J, Muro K, Al‐Batran SE, Klempner SJ, Wainberg ZA, Shah MA, Rha SY, Ohtsu A, Liepa AM, Knoderer H, Chatterjee A, Van Cutsem E. Toward a Treatment Sequencing Strategy: A Systematic Review of Treatment Regimens in Advanced Gastric Cancer/Gastroesophageal Junction Adenocarcinoma. Oncologist 2021; 26:e1704-e1729. [PMID: 34288262 PMCID: PMC8488781 DOI: 10.1002/onco.13907] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Accepted: 07/02/2021] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND Platinum and fluoropyrimidine combinations typically comprise first-line (1L) therapy in advanced gastric cancer or gastroesophageal junction adenocarcinoma (G/GEA), although controversy exists regarding the use of 5doublet versus triplet cytotoxic regimens. Historically, second-line (2L) and third-line or later (3L+) therapy has been fragmented. Recent trials have increased the need for optimal treatment sequencing in advanced G/GEA. MATERIALS AND METHODS We conducted a systematic search of peer-reviewed manuscripts of randomized clinical trials examining 1L, 2L, and 3L+ therapy for advanced G/GEA published from 2009 through November 19, 2019. When available, overall survival, progression-free survival, time to progression, overall response rate, and toxicity were extracted from each and compared descriptively. RESULTS In 1L therapy, chemotherapy triplets demonstrated variable efficacy improvements with invariable increased toxicity compared with platinum/fluoropyrimidine doublets. Currently, the only published report of positive outcomes using biologics in 1L describes adding trastuzumab in HER2-overexpressing advanced G/GEA. In 2L, doublet chemotherapy regimens are not uniformly more efficacious than single-agent taxanes or irinotecan, and ramucirumab has demonstrated improved outcomes both as monotherapy and in combination. CONCLUSION For advanced G/GEA, review of trial results from 2009-2019 support 1L therapy with platinum and fluoropyrimidine and sequencing with taxanes or irinotecan in combination with biologics as effective 2L options. Escalating to a triplet may add some efficacy at the expense of added toxicity. IMPLICATIONS FOR PRACTICE The rapidly changing treatment landscape for advanced gastric cancer includes increasing options for refractory disease. With multiple first-line platinum-based regimens, identification of those with the best benefit-to-risk ratio may provide guidance on treatment sequencing strategies. This article presents findings from the published literature of randomized controlled trials that included a first-line platinum/fluoropyrimidine combination and, for second-line trials, patients with platinum/fluoropyrimidine-refractory disease. This guiding summary could be a tool for clinicians to identify the optimal first-line regimen(s) followed by a strategy for subsequent regimens.
Collapse
Affiliation(s)
- Daniel V. Catenacci
- University of Chicago Medical Center & Biological SciencesChicagoIllinoisUSA
| | - Joseph Chao
- City of Hope Comprehensive Cancer CenterDuarteCaliforniaUSA
| | - Kei Muro
- Aichi Cancer Center HospitalNagoyaJapan
| | | | | | | | | | - Sun Young Rha
- Yonsei Cancer Center, Yonsei University College of MedicineSeoulKorea
| | | | | | | | | | - Eric Van Cutsem
- Digestive Oncology, University Hospitals Gasthuisberg Leuven and KU LeuvenLeuvenBelgium
| |
Collapse
|