Checkpoint Inhibitors in the Treatment of Upper Gastrointestinal Tract Tumors
Authors:
R. Obermannová
Authors‘ workplace:
Lékařská fakulta MU, Brno
; Klinika komplexní onkologické péče Masarykova onkologického ústavu, Brno
Published in:
Klin Onkol 2017; 30(Supplementum3): 50-54
Category:
Review
doi:
https://doi.org/14735/amko20173S50
Overview
Chemotherapy prolongs overall survival (OS) in esophageal (EC) and gastric cancer (GC). Unsatisfactory results of systemic therapy initiated a search for new treatment options. In metastatic disease, a number of targeted drugs were tested; however, several phase III studies assessing receptor tyrosin kinase-related signaling pathways, such as EGFR, MET/HGF or mTOR, failed. Trastuzumab remains the only targeted drug with a known molecular predictor, which extended the OS in metastatic gastric adenocarcinoma and adenocarcinoma of esophago-gastric junction. In the past two years, The Cancer Genome Atlas group published an analysis based on the genomic characteristics of GC and EC. Therefore, a better understanding of tumor biology may be a way towards stratification of treatment based on genetic and molecular characteristics and not merely on anatomical or histological basis. The rapid development in research of anti-tumor immunity and an achievement in the field of checkpoint inhibitors use in malignant melanoma have also enabled research in other cancers, including gastrointestinal malignancies. Checkpoints are part of a comprehensive and complex process of the immune system, and at the same time, the key points in the emergence of tumor tolerance. Their activation protects the organism against autoimmune reactions, but at the same time allows induction of tumor tolerance. Discussing checkpoints include the cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death-1 (PD-1) receptors and the ligand PD-1 receptor, programmed death ligand-1 (PD-L1). In this article, I summarize current findings on the use of anti PD1 agents in EC and GC.
Key words:
esophageal cancer – stomach cancer – checkpoint inhibitors
This work was supported by the project of Ministry of Health of the Czech Republic No. 15 P03- 17-29389A and by projects LO1413, DRO and LM15089 BBMRI-CZ.
The author declares she has no potential conflicts of interest concerning drugs, products, or services used in the study.
The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.
Submitted:
17. 9. 2017
Accepted:
5. 11. 2017
Sources
1. Ferlay J, Soerjomataram I, Dikshit R et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015; 136 (5): 359–386. doi: 10.1002/ijc.29210.
2. Bang YJ, Van Cutsem E, Feyereislova A et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastrin or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 2010; 376 (9742): 687–697. doi: 10.1016/S0140-6736 (10) 61121-X.
3. Freeman GJ, Long AJ, Iwai Y et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 2000; 192 (7): 1027–1034.
4. Raufi AG, Klempner SJ. Immunotherapy for advanced gastric and esophageal cancer: preclinical rationale and ongoing clinical investigations. J Gastrointest Oncol 2015; 6 (5): 561–569. doi: 10.3978/j.issn.2078-6891.2015.037.
5. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature 2014; 513 (7517): 202–209. doi: 10.1038/nature13480.
6. Abdel-Rahman O. Immune checkpoints aberrations and gastric cancer; assessment of prognostic value and evaluation of therapeutic potentials. Crit Rev Oncol Hematol 2016; 97: 65–71. doi: 10.1016/j.critrevonc.2015.08. 015.
7. Thompson ED, Zahurak M, Murphy A et al Patterns of PD-L1 expression and CD8 T cell infiltration in gastric adenocarcinomas and associated immune stroma. Gut 2016; 66 (5): 794–801. doi: 10.1136/gutjnl-2015-310839.
8. Muro K, Chung HC, Shankaran V et al. Pembrolizumab for patients with PD-L1-positive advanced gastric cancer (KEYNOTE-012): a multicentre, open-label, phase 1b trial. Lancet Oncol 2016; 17 (6): 717–726. doi: 10.1016/S1470-2045 (16) 00175-3.
9. Fuchs CS, Doi T, Woo-Jun Jang R et al. KEYNOTE-059 cohort 1: Efficacy and safety of pembrolizumab (pembro) monotherapy in patients with previously treated advanced gastric cancer. J Clin Oncol 2017; 35 (Suppl 15): abstr. 4003.
10. Le DT, Uram JN, Wang H et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 2015; 372 (26): 2509–2520. doi: 10.1056/NEJMoa1500596.
11. Janjigian YY, Bendell JC, Calvo E et al. CheckMate-032: phase I/II, openlabel study of safety and activity of nivolumab (nivo) alone or with ipilimumab (ipi) in advanced and metastatic (A/M) gastric cancer (GC). J Clin Oncol 2016; 34 (Suppl 15): abstr. 4010.
12. Kang YK, Satoh T, Ryu MH et al. Nivolumab (ONO-4538/BMS-936558) as salvage treatment after 2nd or later line chemotherapy for advanced gastric or gastroesophageal junction cancer (AGC): a double-blinded, randomized phase III trial. J Clin Oncol 2017; 35 (Suppl 4): abstr 2. doi: 10.1200/JCO.2017.35.4_suppl.2.
13. Yamada Y, Nishina T, Iwasa S et al. A phase I dose expansion trial of avelumab (MSB0010718C), an anti-PD-L1 antibody, in Japanese patients with advanced gastric cancer. J Clin Oncol 2015; 33 (Suppl 15): abstr 4047.
14. Chung HC, Arkenau HT, Wyrwicz L et al. Avelumab (MSB0010718C; anti-PD-L1) in patients with advanced gastric or gastroesophageal junction cancer from JAVELIN solid tumor phase Ib trial: analysis of safety and clinical activity. J Clin Oncol 2016; 34 (Suppl 15): abstr. 4009.
15. Le DT, Uram JN, Wang H et al. PD-1 blockade in tumors with mismatch repair deficiency. N Engl J Med 2015; 372 (26): 2509–2520. doi: 10.1056/NEJMoa1500596.
16. Registrar Corp.com. [online]. Available from: https: //www.fda.gov/drugs/informationondrugs/approveddrugs/ucm558048.htm.
17. Hellman MD, Rizvi NA, Goldman JW et al. Nivolumab plus ipilimumab as first-line treatment for advanced non-small-call lung cancer (Check Mate 012): results from an open-label, phase I, multicohort study. Lancet Oncol 2017; 18 (1): 31–41. doi: 10.1016/S1470-2045 (16) 30624-6.
18. Hato SV, A Khong A, de Vries IJ et al. Molecular pathways: The immunogenic effects of platinum-based chemotherapeutics. Clin Cancer Res 2014; 20 (11): 2831–2837. doi: 10.1158/1078-0432.CCR-13-3141.
19. Bang YJ, Muro K, Fuchs CS et al. KEYNOTE-059 cohort 2: Safety and efficacy of pembrolizumab (pembro) plus 5-fluorouracil (5-FU) and cisplatin for first-line (1L) treatment of advanced gastric cancer. J Clin Oncol 2017; 35 (Suppl 15): abstr. 4012.
20. Herbst RS, Bendell JC, Isambert N et al. A phase 1 study of ramucirumab (R) plus pembrolizumab (P) in patients (pts) with advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma, non-small cell lung cancer (NSCLC), or urothelial carcinoma (UC): phase 1a results. J Clin Oncol 2016; 34 (Suppl 15): abstr. 3056.
21. Smyth EC, Wotherspoon A, Peckitt C et al. Mismatch Repair Deficiency, Microsatellite Instability, and Survival An Exploratory Analysis of the Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) Trial. JAMA Oncol 2017; 3 (9): 1197–1203. doi: 10.1001/jamaoncol.2016.6762.
22. Ohigashi Y, Sho M, Yamada Y et al. Clinical significance of programmed death-1 ligand-1 and programmed death-1 ligand-2 expression in human esophageal cancer. Clin Cancer Res 2005; 11 (8): 2947–2953. doi: 10.1158/1078-0432.CCR-04-1469.
23. Doi T, Piha-Paul SA, Jalal SI et al: Updated results for the advanced esophageal carcinoma cohort of the phase Ib KEYNOTE-028 study of pembrolizumab (MK-3475). J Clin Oncol 2016; 34 (Suppl 4): abstr. 7.
24. Kudo T, Hamamoto Y, Kato K et al. Nivolumab treatment for oesophageal squamous-cell carcinoma: an open-label, multicentre, phase 2 trial. Lancet Oncol 2017; 18 (5): 631–639. doi: 10.1016/ S1470-2045 (17) 30181-X.
Labels
Paediatric clinical oncology Surgery Clinical oncologyArticle was published in
Clinical Oncology
2017 Issue Supplementum3
Most read in this issue
- Evaluation of Inflammatory Cells (Tumor Infiltrating Lymphocytes) in Solid Tumors
- Comparison of RECIST 1.1 and iRECIST for Response Evaluation in Solid Tumours
- Immunotherapy of Colorectal and Anal Carcinoma
- Imunoterapie v léčbě karcinomu plic